The interleukin-2 family (also called the common gamma chain cytokine family) consists of interleukin (IL)2, IL9, IL15 and IL21. Although sometimes considered to be within this family, the IL4 and IL7 receptors can form complexes with other receptor chains and are represented separately in Reactome. Receptors of this family associate with JAK1 and JAK3, primarily activating STAT5, although certain family members can also activate STAT1, STAT3 or STAT6.
View original pathway at:Reactome.
Zhu MH, Berry JA, Russell SM, Leonard WJ.; ''Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to Il-2Rbeta.''; PubMedEurope PMCScholia
Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA.; ''Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor.''; PubMedEurope PMCScholia
Strengell M, Matikainen S, Sirén J, Lehtonen A, Foster D, Julkunen I, Sareneva T.; ''IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.''; PubMedEurope PMCScholia
Zhou YJ, Magnuson KS, Cheng TP, Gadina M, Frucht DM, Galon J, Candotti F, Geahlen RL, Changelian PS, O'Shea JJ.; ''Hierarchy of protein tyrosine kinases in interleukin-2 (IL-2) signaling: activation of syk depends on Jak3; however, neither Syk nor Lck is required for IL-2-mediated STAT activation.''; PubMedEurope PMCScholia
Evans GA, Goldsmith MA, Johnston JA, Xu W, Weiler SR, Erwin R, Howard OM, Abraham RT, O'Shea JJ, Greene WC.; ''Analysis of interleukin-2-dependent signal transduction through the Shc/Grb2 adapter pathway. Interleukin-2-dependent mitogenesis does not require Shc phosphorylation or receptor association.''; PubMedEurope PMCScholia
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
Chi F, Chen L, Wang C, Li L, Sun X, Xu Y, Ma T, Liu K, Ma X, Shu X.; ''JAK3 inhibitors based on thieno[3,2-d]pyrimidine scaffold: design, synthesis and bioactivity evaluation for the treatment of B-cell lymphoma.''; PubMedEurope PMCScholia
Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, Beckius GE, Moyer JD, Su C, Woodworth TG, Gaweco AS, Beals CR, Littman BH, Fisher DA, Smith JF, Zagouras P, Magna HA, Saltarelli MJ, Johnson KS, Nelms LF, Des Etages SG, Hayes LS, Kawabata TT, Finco-Kent D, Baker DL, Larson M, Si MS, Paniagua R, Higgins J, Holm B, Reitz B, Zhou YJ, Morris RE, O'Shea JJ, Borie DC.; ''Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.''; PubMedEurope PMCScholia
Sim GC, Radvanyi L.; ''The IL-2 cytokine family in cancer immunotherapy.''; PubMedEurope PMCScholia
Vallières F, Girard D.; ''Mechanism involved in interleukin-21-induced phagocytosis in human monocytes and macrophages.''; PubMedEurope PMCScholia
Ravichandran KS, Burakoff SJ.; ''The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K.; ''The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.''; PubMedEurope PMCScholia
Lin JX, Mietz J, Modi WS, John S, Leonard WJ.; ''Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells.''; PubMedEurope PMCScholia
Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMedEurope PMCScholia
Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S.; ''IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Salcini AE, McGlade J, Pelicci G, Nicoletti I, Pawson T, Pelicci PG.; ''Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins.''; PubMedEurope PMCScholia
Harkiolaki M, Tsirka T, Lewitzky M, Simister PC, Joshi D, Bird LE, Jones EY, O'Reilly N, Feller SM.; ''Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2.''; PubMedEurope PMCScholia
Friedmann MC, Migone TS, Russell SM, Leonard WJ.; ''Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation.''; PubMedEurope PMCScholia
Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMedEurope PMCScholia
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Winthrop KL.; ''The emerging safety profile of JAK inhibitors in rheumatic disease.''; PubMedEurope PMCScholia
Rickert M, Boulanger MJ, Goriatcheva N, Garcia KC.; ''Compensatory energetic mechanisms mediating the assembly of signaling complexes between interleukin-2 and its alpha, beta, and gamma(c) receptors.''; PubMedEurope PMCScholia
Habib T, Senadheera S, Weinberg K, Kaushansky K.; ''The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3.''; PubMedEurope PMCScholia
Li H, Rostami A.; ''IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity.''; PubMedEurope PMCScholia
Behrmann I, Janzen C, Gerhartz C, Schmitz-Van de Leur H, Hermanns H, Heesel B, Graeve L, Horn F, Tavernier J, Heinrich PC.; ''A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation.''; PubMedEurope PMCScholia
Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK.; ''The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.''; PubMedEurope PMCScholia
Rosenthal LA, Winestock KD, Finbloom DS.; ''IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.''; PubMedEurope PMCScholia
Sánchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutiérrez-Ramos JC, Coyle AJ, Strom TB.; ''Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.''; PubMedEurope PMCScholia
Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMedEurope PMCScholia
Miyazaki T, Takaoka A, Nogueira L, Dikic I, Fujii H, Tsujino S, Mitani Y, Maeda M, Schlessinger J, Taniguchi T.; ''Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway.''; PubMedEurope PMCScholia
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMedEurope PMCScholia
Neurath MF, Finotto S.; ''IL-9 signaling as key driver of chronic inflammation in mucosal immunity.''; PubMedEurope PMCScholia
Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA.; ''Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity.''; PubMedEurope PMCScholia
Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ.; ''Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2.''; PubMedEurope PMCScholia
Lamkin TD, Walk SF, Liu L, Damen JE, Krystal G, Ravichandran KS.; ''Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP.''; PubMedEurope PMCScholia
Minami Y, Nakagawa Y, Kawahara A, Miyazaki T, Sada K, Yamamura H, Taniguchi T.; ''Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway.''; PubMedEurope PMCScholia
Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K.; ''Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex.''; PubMedEurope PMCScholia
Rochman Y, Spolski R, Leonard WJ.; ''New insights into the regulation of T cells by gamma(c) family cytokines.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
Nizsalóczki E, Csomós I, Nagy P, Fazekas Z, Goldman CK, Waldmann TA, Damjanovich S, Vámosi G, Mátyus L, Bodnár A.; ''Distinct spatial relationship of the interleukin-9 receptor with interleukin-2 receptor and major histocompatibility complex glycoproteins in human T lymphoma cells.''; PubMedEurope PMCScholia
Flanagan ME, Blumenkopf TA, Brissette WH, Brown MF, Casavant JM, Shang-Poa C, Doty JL, Elliott EA, Fisher MB, Hines M, Kent C, Kudlacz EM, Lillie BM, Magnuson KS, McCurdy SP, Munchhof MJ, Perry BD, Sawyer PS, Strelevitz TJ, Subramanyam C, Sun J, Whipple DA, Changelian PS.; ''Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.''; PubMedEurope PMCScholia
Naeger LK, McKinney J, Salvekar A, Hoey T.; ''Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD.; ''Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15.''; PubMedEurope PMCScholia
Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T.; ''Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.''; PubMedEurope PMCScholia
Ravichandran KS, Igras V, Shoelson SE, Fesik SW, Burakoff SJ.; ''Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
Gadina M, Sudarshan C, Visconti R, Zhou YJ, Gu H, Neel BG, O'Shea JJ.; ''The docking molecule gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines.''; PubMedEurope PMCScholia
Brockdorff JL, Gu H, Mustelin T, Kaltoft K, Geisler C, Röpke C, Ødum N.; ''Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and Stat5a.''; PubMedEurope PMCScholia
Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O.; ''Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID.''; PubMedEurope PMCScholia
Clark JD, Flanagan ME, Telliez JB.; ''Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.''; PubMedEurope PMCScholia
Harmer SL, DeFranco AL.; ''The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes.''; PubMedEurope PMCScholia
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Nelson BH, Lord JD, Greenberg PD.; ''Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation.''; PubMedEurope PMCScholia
Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D, Khan N, Veldman G, Jacobs KA, Valge-Archer VE, Collins M, Carreno BM.; ''Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses.''; PubMedEurope PMCScholia
Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ.; ''Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain.''; PubMedEurope PMCScholia
Gu H, Pratt JC, Burakoff SJ, Neel BG.; ''Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation.''; PubMedEurope PMCScholia
Odai H, Sasaki K, Iwamatsu A, Nakamoto T, Ueno H, Yamagata T, Mitani K, Yazaki Y, Hirai H.; ''Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl.''; PubMedEurope PMCScholia
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMedEurope PMCScholia
Landgraf BE, Goldstein B, Williams DP, Murphy JR, Sana TR, Smith KA, Ciardelli TL.; ''Recombinant interleukin-2 analogs. Dynamic probes for receptor structure.''; PubMedEurope PMCScholia
Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC.; ''Engagement of Gab1 and Gab2 in erythropoietin signaling.''; PubMedEurope PMCScholia
Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH, Neel BG.; ''New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway.''; PubMedEurope PMCScholia
Ingham RJ, Okada H, Dang-Lawson M, Dinglasan J, van Der Geer P, Kurosaki T, Gold MR.; ''Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase.''; PubMedEurope PMCScholia
Wang X, Lupardus P, Laporte SL, Garcia KC.; ''Structural biology of shared cytokine receptors.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks
The high affinity Interleukin-15 receptor is a heterotrimer of Interleukin-15 receptor subunit alpha (IL15RA), Interleukin-2 receptor subunit beta (IL2RB, CD122) and Cytokine receptor common subunit gamma (IL2RG, CD132). IL2RB and IL2RG are also components of the Interleukin-2 (IL2) receptor. Treatment of human T cells with Interleukin-15 (IL15) results in tyrosine phosphorylation of Tyrosine-protein kinase JAK1 (JAK1, Janus kinase 1) and Tyrosine-protein kinase JAK3 (JAK3, Janus kinase 3) (Johnston et al. 1995, Winthrop 2017). IL15 can signal by a process termed 'trans presentation', where IL15 bound by IL15 on one cell is trans-presented to IL2RB:IL2RG on another cell (Dubois et al. 2002) but can also participate in more 'traditional' cis signaling (Wu et al. 2008, Mishra et al. 2014) where all the three receptors are present on the same cell.
Stimulation of lymphocytes by IL15 release MAPK activation through GAB2/SHP2/SHC (GRB2-associated-binding protein 2/Tyrosine-protein phosphatase non-receptor type 11/SHC transforming protein 1 or 2) cascade activation (Gadina et al. 2000).
Interleukin 9 (IL9) binds interleukin 9 receptor a chain (IL9R) and the interleukin 2 receptor common gamma chain (IL2RG) to initiate IL9 signaling downstream cascade. IL9R colocalize with Interleukin 2 receptor α chain and MHC molecules in lipid rafts of human T lymphoma cells (Nizsalóczki et al. 2014). IL2RG is essential for IL9 dependent growth signal transduction (Kimura et al. 1995). IL9R (glycoprotein of 64 kDa) has saturable and specific binding sites with a Kd of 100 pM (Renauld et al. 1992). The activated IL9R complex recruits tyrosine kinase proteins from the Janus kinase (JAK) family: JAK1 (JAK1) and JAK3 (JAK3) for subsequent activation of the Signal transducer and activator of transcription (STAT) factors STAT1, STAT3 and STAT5. The activated STATs form STAT5 dimers and STAT1:STAT3 heterodimers (Neurath & Finotto 2016, Li & Rostami 2010).
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
This set represents Class 1A PI3Ks including all three genes that can give rise to the five isoforms of the regulatory subunit. Note that the p85 alpha form is almost always the form used as a reagent experimentally and measured by p85-Abs.The other forms are rarely used or determined experimentally. Also note that Class 1A PI3Ks may not be the most relevant physiologically in some cell types (e.g. T cells).
There are five variants of the p85 regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta, and p55gamma. There are also three variants of the p110 catalytic subunit designated p110alpha, beta, or gamma catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (Pik3r1), the other two are expressed by Pik3r2 and Pik3r3, respectively). The most highly expressed regulatory subunit is p85alpha. All three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb, and Pik3cd for p110alpha, p110beta and p110gamma, respectively). The alpha and beta p110s are expressed in all cells, while p110gamma is expressed primarily in leukocytes. It has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p101 and catalytic p110gamma subunits comprise the class IB PI3Ks, each is encoded by a single gene.
The crystal structure of the assembled IL2:IL2 receptor complex and experiments using isothermal titration calorimetry suggest that the complex of IL2 with IL2R alpha is likely to preferentially associate with IL2R bet (Rickert et al. 2004, Stauber et al. 2006). Binding of IL-2/IL-2R alpha to IL-2R beta significantly slows the dissociation of IL-2. However, the trimeric complex of IL-2:IL-2R alpha:IL-2R beta is incapable of signaling without participation of the gamma chain.
The interleukin-2 receptor is a heterotrimer composed of interleukin-2 receptor alpha (IL2RA), beta (IL2RB) and gamma (IL2RG) subunits. Individually, IL2RA and IL2RB have low affinity for interleukin-2 (IL2); IL2RG has very low affinity. The IL2RA chain has a short cytoplasmic domain and consequently does not transmit an intracellular signal, but it binds IL-2 with high affinity and is required in vivo for detection of physiological IL-2 levels (Kd for IL-2RB/G = 10-9 M versus 10-11 M for IL-2RA/B/G, Takeshita et al. 1992). The crystal structure of the trimeric complex bound to IL2 suggests that the initiating event is the binding of IL2 to IL2R alpha (Wang et al. 2005). This captures IL2 at the cell surface and allows the recruitment of the beta and gamma subunits, which then participate in signal transduction.
IL-2R alpha chains are expressed at much greater levels than the other receptor chains, usually 10-1000-fold higher compared with IL-2R beta or gamma (~1,000 sites/cell), which are usually expressed in equal numbers (Smith & Cantrell 1985). Recent single cell analysis methods have found that as the density of IL-2R alpha chains varies 1,000-fold from 100 to 100,000 sites/cell, the equilibrium dissociation constant of IL-2 binding varies to the same extent, from 100 pM to 100 fM, with the consequence that as the density of IL-2R alpha chains increases there is a marked improvement in IL-2 binding efficiency and thus signaling (Feinerman O et al. 2010). IL-2 binding to IL-2Ralpha is rapid on and rapid off.
Recruitment of the IL-2R gamma chain forms a very stable quaternary complex, capable of signaling. The IL-2 gamma chain further retards IL-2 dissociation so that the rate of IL-2 dissociation from the complex is three times slower than the rate of internalization of the complex (t1/2 55= 45 min vs. 15 min). Therefore, the complex continues to signal as long as it remains on the cell surface.
Cytokine receptor common gamma subunit (IL2RG, IL-2 receptor gamma chain, Gc) associates with Tyrosine-protein kinase JAK3 (JAK3). The carboxyl-terminal region of IL2RG is important for this association (Miyazaki et al. 1994, Zhu et al. 1998, Russel et al. 2004, Chen et al.1997, Nelson et al.1994) as well as the FERM domain in JAK3 (Zhou et al. 2001).
Receptor activation involves JAK1 and JAK3 as T-cells from mice lacking either kinase are unable to respond to cytokines that utilize the Common gamma chain (Rodig et al. 1998, Park et al. 1995). Naturally occurring JAK3 mutations prevent binding to the Interleukin-2 receptor, leading to severe immunodeficiency due to a lack of signaling (Macchi et al. 1995, Russell et al. 1995). Mechanistic models of receptor activation suggest that assembly of the quaternary receptor and the consequent proximity of JAK1 and JAK3, bound to the cytoplasmic domains of the beta and gamma chains, is the trigger for JAK activation (Ellery et al. 2000). JAK3 is thought to activate JAK1, as JAK3 does not require tyrosine phosphorylation to activate its kinase activity (Liu et al. 1997), and JAK3 has been demonstrated to phosphorylate JAK1 in response to IL-2 (Kawahara et al. 1995). JAK3 also becomes phosphorylated in response to IL-2 (Johnston et al. 1994), either by JAK1 trans-activation or by an indirect mechanism. The activated JAKs then phosphorylate critical tyrosine residues within IL2RB.
Phosphorylation of IL2RB Y338 creates a binding site for the accessory protein SHC, which then becomes tyrosine phosphorylated and recruits the Grb2/Sos and Grb2:Gab2 complexes.
STAT5 alpha and beta are recruited to the receptor complex and phosphorylated. JAK3 is believed to be responsible for the tyrosine phosphorylation of STAT5 in response to IL-2; it is not clear whether JAK1 is also involved (Lin & Leonard, 2000). Tyr-694 of STAT5a and Tyr-699 of STAT5b are required for IL-2 induced STAT5 activation (Lin et al. 1996). STAT5a and STAT5b are also known to be serine phosphorylated in lymphocytes activated by IL-2 but the funtion of this is unclear (Xue et al. 2002).
Following IL2 stimulation of IL2R, Shc is known to be tyrosine phosphorylated (Zhu et al. 1994). The identity of the kinase is uncertain (Gesbert et al. 1998); JAK1 may be responsible but this has not been demonstrated, another candidate is Lck.
Following IL-3 treatment, Shc becomes tyrosyl phoshorylated at 3 sites, Y427 (Salcini et al. 1994), Y349 and Y350 (Gotoh et al. 1996). Y427 mediates the subsequent association with Grb2 (Salcini et al. 1994).
Numbering here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references used here refer to the p52 isoform which lacks the first 110 residues, so Y427 is referred to as Y317 in Salcini et al. 1994, Y349 and Y350 as Y239 and Y240 in Gotoh et al. 1996.
Phosphorylated STAT5A and STAT5B form homodimers and heterodimers in the cytosol (Gaffen et al. 1996, Rosenthal et al. 1997, also inferred from mouse homologs). Phosphorylation of a critical tyrosine residue in the SH domain (Y694 in STAT5A and Y699 in STAT5B) and intramolecular interactions between hydrophobic residues in the SH domain are required for dimerization (inferred from mouse homologs).
Mutation analysis has shown that Y338, Y392 and Y510 are involved in IL-2-induced STAT protein binding. Phospho-tyrosines 338, 392 and 510 can each promote STAT5 activation (Gaffen et al. 1996), though Y510 appears to be the primary site for STAT5 binding (Gesbert et al. 1998). STAT3 may also be recruited to phospho-tyrosines on IL2RB and studies have shown defective IL-2 responses in STAT3-/- T cells, thereby supporting a functional role for STAT3 downstream of IL-2 signaling (Akaishi et al. 1998).
Following stimulation by IL2, the IL2R beta chain become phosphorylated on multiple tyrosine residues. These phosphotyrosine residues recruit position-specific signaling or adaptor proteins, leading to the activation of downstream signaling pathways. Although multiple kinases are involved in the phosphorylation of IL-2R beta, JAK1-dependent phosphorylation of tyrosines 338, 392 and 510 is known to be involved in STAT protein binding (Gaffen et al. 1996). Phospho-tyrosine 338 has also been shown to participate in recruitment and subsequent phosphorylation of the adaptor Shc (Friedmann et al. 1996). N.B. Numbering in the literature is based on the mature peptide, with the 26 residue signal peptide removed. Positions given in this reaction refer to the canonical Uniprot sequence, e.g. 338 is equivalent to 364 of the canonical sequence P14784.
Phosphorylated Shc recruits Grb2 and Gab2, probably by binding to Grb2 in the Grb2:Gab2 complex. Gab2 associates with Grb2, Shc, Shp2 and the p85 subunit of PI3K (Gu et al. 1998). The association of Grb2 with Gab2 has been suggested to be constitutive (Gu et al. 2000, Kong et al. 2003, Harkiolaki et al. 2009), so Gab2 may be recruited to Shc1 with Grb2. Alternatively, Gab2 has been suggested to associate constitutively with Shc (Kong et al 2003). In either case, the result is a complex of Shc:Grb2:Gab2. Gab2 binding to p85 (Gu et al. 1998) links Shc1 to PI3K activity and subsequent activation of kinases such as Akt (Gu et al. 2000).
Shc is tyrosine phosphorylated by an unidentified kinase, creating a docking site for the SH2 domain of Grb2 (Zhu et al. 1994). Grb2 is an adaptor protein believed to be constitutively associated with the guanine nucleotide exchange protein Sos1 (often abbreviated to Sos). Recruitment of the Grb2:Sos1 complex leads to activation of the Ras pathway (Ravichandran & Burakoff 1994) and consequently activation of the MAPK pathway.
Interleukin-7 (IL7)-activated Signal transducer and activator of transcription 5A or 5B (typically referred to as STAT5) is recruited rapidly to the promoters of IL7-regulated genes (Ye et al. 2001, Stanton & Brodeur 2005).
Shc promotes Gab2 tyrosine phosphorylation via Grb2 (Gu et al. 2000). This promotes binding of Gab2 to p85alpha, a component of Class 1A PI3Ks (Gu et al. 1998). JAK1 may also be involved in PI3K recruitment (Migone et al. 1998). Binding of p85 activates PI3K kinase activity, with consequent effects on many processes including Akt activation. This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors, the other is mediated by Serine-585 phosphorylation of the common beta chain.
Studies have shown that coexpression of Syk with catalytically active Jak1 results in Syk phosphorylation whereas coexpression of Syk with catalytically active Jak3 does not, suggesting that IL-2 driven phosphorylation of Syk is driven by Jak1 (Zhou et al. 2000).
Syk binds to the serine-rich (aa 267 to 322) S region of IL2RB and becomes activated upon IL-2 stimulation (Minami et al. 1995). Syk is shown here binding with the IL2:IL2RB trimer:p-JAK1:JAK3 complex but it may become associated at an earlier stage of receptor activation.
The proline rich tyrosine kinase 2 (PYK2) is a nonreceptor protein tyrosine kinase that is structurally related to FAK and thought to be important for leukocyte activation (Ostergaard & Lysechko, 2005). PYK2 tyrosine phosphorlation is known to occur downstream of IL-2 stimulation in human peripheral T lymphocytes. This phosphorylation can be prevented by blocking IL-2 mediated JAK activity. Although the function of Pyk2 within the IL-2 signaling pathways remains uncertain, a dominant negative mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation which suggests that Pyk2 does indeed influence IL-2 driven immune cell responses.
The proline-rich tyrosine kinase 2 (PYK2) is a nonreceptor protein tyrosine kinase that is structurally related to FAK and thought to be important for leukocyte activation (Ostergaard & Lysechko 2005). Coimmunoprecipitation experiments have demonstrated a physical association of Jak3 and Pyk2. A dominant interfering mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation. Collectively, these results suggest that Pyk2 is a component of the Jak-mediated IL-2 signaling pathway, but a role has not been firmly established.
T-helper (Th) cell-mediated immunity is required to eliminate pathogens effectively but unrestrained Th activity can contribute to tissue damage in many inflammatory and autoimmune diseases. The T-cell immunoglobulin and mucin domain-containing protein (HAVCR2, TIM3) inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and allo-immune responses and promotes immunological tolerance when it binds to its ligand, galectin-9 (LGALS9). The HAVCR2:LGALS9 complex achieves this inhibition by inducing apoptosis of Th1 cells. The human event is inferred from experimental data from mouse studies (Sanchez-Fueyo et al. 2003, Zhu et al. 2005).
Interleukin-21 (IL21) is a pleiotropic cytokine with four alpha-helical bundles. It is produced primarily by natural killer T cells, T follicular helper cells and TH17 cells, with lower levels of production by numerous other populations of lymphohaematopoietic cells (Spolski & Leonard 2014). IL21 binds Interleukin-21 receptor (IL21R, NILR) and Cytokine receptor common subunit gamma (IL2RG, GammaC). IL21R has significant homology with the class I cytokine receptors Interleukin-2 receptor subunit beta (IL2RB) and Interleukin-4 receptor subunit alpha (IL4R) and was predicted to similarly form a complex with IL2RG. IL21R dimers can weakly bind and signal in response to IL21 but IL21 generates a much stronger response when IL21R is combined with IL2RG, which is required for a fully signaling capable IL21 receptor complex (Ozaki et al. 2000, Asao et al. 2001, Habib et al. 2002). IL21R can bind Janus kinase 1 (JAK1) (Ozaki et al. 2000) but IL2RG is required for IL21 induced signaling (Asao et al. 2001). The heteromeric IL21 receptor complex can activate JAK1, JAK3, Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2017).
This is a black-box event because the pre-association of IL21R with JAK1 is inferred from the constitutive association of JAKs with other interleukin receptor subunits such as IL2R.
Interleukin-21 receptor (IL21R, NILR) can bind Janus kinase 1 (JAK1) (Ozaki et al. 2000) but little or no signaling occurs (Asao et al. 2001) unless IL21R is combined with IL2RG, which is required for a fully signaling capable IL21 receptor complex (Ozaki et al. 2000, Asao et al. 2001, Habib et al. 2002). The heteromeric IL21 receptor complex can activate JAK1 and JAK3.
This is a black box event because the pre-association of IL21R with JAK1 and of IL2RG with JAK3 is inferred from the mechanism of IL2 signaling.
The IL21 heteromeric receptor complex can activate JAK1 and JAK3 in response to Interleukin-21 (IL21), leading to JAK tyrosine phosphorylation (Asao et al. 2001, Habib et al. 2002).
This is a black box event because the mechanism leading to JAK phosphorylation is not established for this receptor complex.
The IL21R:IL2RG complex can activate Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2016).
The IL21 receptor complex can activate Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2016).
This is a black-box event because STAT phosphorylation is assumed to involve STAT binding though this has not been demonstrated for this receptor complex. In addition the mechanism that brings about STAT binding to the receptor, which presumably involves receptor tyrosine phosphorylation, is unclear.
Binding of Gab2 to tyrosine phosphorylated Shc promotes the phosphorylation of Gab2 by an unknown kinase. Gab2 becomes tyrosine phosphorylated in response to IL-2 (Brockdorff et al. 2001) and IL-3 (Gu et al. 1998). Chimeric receptors were used to demonstrate that Shc is sufficient for Gab2 tyrosine phosphorylation. In response to IL-3, Grb2 was also required, reflecting that Gab2 is recruited to the activated cytokine receptor complex as a complex of Gab2:Grb2 (Gu et al. 2000).
SHIP dephosphorylates PIP3 and may limit the magnitude or duration of signaling events that are dependent upon PIP3-mediated membrane recruitment of plextrin homology (PH) domain signalling proteins such as PI3K and Akt (Aman et al. 1998). The PTB domain of SHC1 binds to phosphorylated tyrosine residues on SHIP. Mutations that inactivate the PTB domain prevent this binding and substitution of F for Y917 and Y1020 on SHIP prevents creation of the phosphotyrosine motifs that are recognized by the SHC1 PTB domain, blocking the interaction (Lamkin et al. 1997). A functional SHIP SH2 domain is also reported as a requirement for association of SHIP with Shc (Liu et al. 1997). GRB2 stabilizes the SHC1/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on SHC1, forming a ternary complex of SHC1:GRB2:SHIP described as inducible by IL-3, IL-5 or GM-CSF by many authors (Jucker et al. 1997, Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999).
Grb2 stabilizes the Shc/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on Shc. This forms a ternary complex of SHC1:GRB2:SHIP described as an outcome of IL-3, IL-5 or GM-CSF stimulation (Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999).
Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
trimer p-(Y338,392,510) beta
subunit:p-JAK1:JAK3:STAT5trimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHCtrimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHCtrimer p-(Y338,Y392, Y510) beta
subunit:p-JAK1:JAK3:p-STAT5p-(Y338,392,510) beta
subunit:p-JAK1:JAK3receptor complexes with activated
Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Kscompexes with activated
Shc:GRB2:GAB2complexes with activated
SHC1:GRB2:SOS1complexes with activated
SHC1:SHIP1,2complexes with activated
SHC1:SHIP1complexes with activated
SHC1:SHIP:GRB2complexes with activated
Shc:GRB2:p-GAB2complexes with
activated SHC1The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
Annotated Interactions
trimer p-(Y338,392,510) beta
subunit:p-JAK1:JAK3:STAT5trimer p-(Y338,392,510) beta
subunit:p-JAK1:JAK3:STAT5trimer p-(Y338,392,510) beta
subunit:p-JAK1:JAK3:STAT5trimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHCtrimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHCtrimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHCtrimer p-(Y338,Y392, Y510) beta
subunit:p-JAK1:JAK3:p-STAT5trimer p-(Y338,Y392, Y510) beta
subunit:p-JAK1:JAK3:p-STAT5p-(Y338,392,510) beta
subunit:p-JAK1:JAK3p-(Y338,392,510) beta
subunit:p-JAK1:JAK3p-(Y338,392,510) beta
subunit:p-JAK1:JAK3p-(Y338,392,510) beta
subunit:p-JAK1:JAK3receptor complexes with activated
Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Kscompexes with activated
Shc:GRB2:GAB2compexes with activated
Shc:GRB2:GAB2complexes with activated
SHC1:GRB2:SOS1complexes with activated
SHC1:SHIP1,2complexes with activated
SHC1:SHIP1complexes with activated
SHC1:SHIP:GRB2complexes with activated
Shc:GRB2:p-GAB2complexes with activated
Shc:GRB2:p-GAB2complexes with
activated SHC1complexes with
activated SHC1complexes with
activated SHC1Following IL-3 treatment, Shc becomes tyrosyl phoshorylated at 3 sites, Y427 (Salcini et al. 1994), Y349 and Y350 (Gotoh et al. 1996). Y427 mediates the subsequent association with Grb2 (Salcini et al. 1994).
Numbering here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references used here refer to the p52 isoform which lacks the first 110 residues, so Y427 is referred to as Y317 in Salcini et al. 1994, Y349 and Y350 as Y239 and Y240 in Gotoh et al. 1996.
Syk is shown here binding with the IL2:IL2RB trimer:p-JAK1:JAK3 complex but it may become associated at an earlier stage of receptor activation.
Coimmunoprecipitation experiments have demonstrated a physical association of Jak3 and Pyk2. A dominant interfering mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation. Collectively, these results suggest that Pyk2 is a component of the Jak-mediated IL-2 signaling pathway, but a role has not been firmly established.
IL21R has significant homology with the class I cytokine receptors Interleukin-2 receptor subunit beta (IL2RB) and Interleukin-4 receptor subunit alpha (IL4R) and was predicted to similarly form a complex with IL2RG. IL21R dimers can weakly bind and signal in response to IL21 but IL21 generates a much stronger response when IL21R is combined with IL2RG, which is required for a fully signaling capable IL21 receptor complex (Ozaki et al. 2000, Asao et al. 2001, Habib et al. 2002). IL21R can bind Janus kinase 1 (JAK1) (Ozaki et al. 2000) but IL2RG is required for IL21 induced signaling (Asao et al. 2001). The heteromeric IL21 receptor complex can activate JAK1, JAK3, Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2017). This is a black-box event because the pre-association of IL21R with JAK1 is inferred from the constitutive association of JAKs with other interleukin receptor subunits such as IL2R.
This is a black box event because the pre-association of IL21R with JAK1 and of IL2RG with JAK3 is inferred from the mechanism of IL2 signaling.
This is a black box event because the mechanism leading to JAK phosphorylation is not established for this receptor complex.
This is a black-box event because STAT phosphorylation is assumed to involve STAT binding though this has not been demonstrated for this receptor complex. In addition the mechanism that brings about STAT binding to the receptor, which presumably involves receptor tyrosine phosphorylation, is unclear.