Semaphorins are a large family of cell surface and secreted guidance molecules divided into eight classes on the basis of their structures. They all have an N-terminal conserved sema domain. Semaphorins signal through multimeric receptor complexes that include other proteins such as plexins and neuropilins.
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Oinuma I, Katoh H, Harada A, Negishi M.; ''Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells.''; PubMedEurope PMCScholia
Raper JA.; ''Semaphorins and their receptors in vertebrates and invertebrates.''; PubMedEurope PMCScholia
Kumanogoh A, Watanabe C, Lee I, Wang X, Shi W, Araki H, Hirata H, Iwahori K, Uchida J, Yasui T, Matsumoto M, Yoshida K, Yakura H, Pan C, Parnes JR, Kikutani H.; ''Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling.''; PubMedEurope PMCScholia
Takegahara N, Takamatsu H, Toyofuku T, Tsujimura T, Okuno T, Yukawa K, Mizui M, Yamamoto M, Prasad DV, Suzuki K, Ishii M, Terai K, Moriya M, Nakatsuji Y, Sakoda S, Sato S, Akira S, Takeda K, Inui M, Takai T, Ikawa M, Okabe M, Kumanogoh A, Kikutani H.; ''Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis.''; PubMedEurope PMCScholia
Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K.; ''GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity.''; PubMedEurope PMCScholia
Gatti A, Huang Z, Tuazon PT, Traugh JA.; ''Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation.''; PubMedEurope PMCScholia
Toyofuku T, Yoshida J, Sugimoto T, Zhang H, Kumanogoh A, Hori M, Kikutani H.; ''FARP2 triggers signals for Sema3A-mediated axonal repulsion.''; PubMedEurope PMCScholia
Leung T, Chen XQ, Manser E, Lim L.; ''The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton.''; PubMedEurope PMCScholia
Tanna AP, Johnson M.; ''Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension.''; PubMedEurope PMCScholia
Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF.; ''Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I.''; PubMedEurope PMCScholia
Billard C, Delaire S, Raffoux E, Bensussan A, Boumsell L.; ''Switch in the protein tyrosine phosphatase associated with human CD100 semaphorin at terminal B-cell differentiation stage.''; PubMedEurope PMCScholia
Swiercz JM, Worzfeld T, Offermanns S.; ''ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1.''; PubMedEurope PMCScholia
Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K.; ''Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase).''; PubMedEurope PMCScholia
Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K, Ihara Y, Mikoshiba K, Kolattukudy P, Honnorat J, Goshima Y.; ''Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease.''; PubMedEurope PMCScholia
Aizawa H, Wakatsuki S, Ishii A, Moriyama K, Sasaki Y, Ohashi K, Sekine-Aizawa Y, Sehara-Fujisawa A, Mizuno K, Goshima Y, Yahara I.; ''Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse.''; PubMedEurope PMCScholia
Edwards DC, Sanders LC, Bokoch GM, Gill GN.; ''Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics.''; PubMedEurope PMCScholia
Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD.; ''Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins.''; PubMedEurope PMCScholia
Ishida I, Kumanogoh A, Suzuki K, Akahani S, Noda K, Kikutani H.; ''Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses.''; PubMedEurope PMCScholia
Herold C, Elhabazi A, Bismuth G, Bensussan A, Boumsell L.; ''CD100 is associated with CD45 at the surface of human T lymphocytes. Role in T cell homotypic adhesion.''; PubMedEurope PMCScholia
Sumi T, Matsumoto K, Nakamura T.; ''Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase.''; PubMedEurope PMCScholia
Li R, Soosairajah J, Harari D, Citri A, Price J, Ng HL, Morton CJ, Parker MW, Yarden Y, Bernard O.; ''Hsp90 increases LIM kinase activity by promoting its homo-dimerization.''; PubMedEurope PMCScholia
Toyofuku T, Yabuki M, Kamei J, Kamei M, Makino N, Kumanogoh A, Hori M.; ''Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1.''; PubMedEurope PMCScholia
Ikebe M, Koretz J, Hartshorne DJ.; ''Effects of phosphorylation of light chain residues threonine 18 and serine 19 on the properties and conformation of smooth muscle myosin.''; PubMedEurope PMCScholia
Ling K, Doughman RL, Firestone AJ, Bunce MW, Anderson RA.; ''Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions.''; PubMedEurope PMCScholia
Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KL.; ''The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG.''; PubMedEurope PMCScholia
Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM.; ''Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates.''; PubMedEurope PMCScholia
Artigiani S, Conrotto P, Fazzari P, Gilestro GF, Barberis D, Giordano S, Comoglio PM, Tamagnone L.; ''Plexin-B3 is a functional receptor for semaphorin 5A.''; PubMedEurope PMCScholia
Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S.; ''The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.''; PubMedEurope PMCScholia
Bernard O, Ganiatsas S, Kannourakis G, Dringen R.; ''Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons.''; PubMedEurope PMCScholia
Barberis D, Casazza A, Sordella R, Corso S, Artigiani S, Settleman J, Comoglio PM, Tamagnone L.; ''p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling.''; PubMedEurope PMCScholia
Vikis HG, Li W, He Z, Guan KL.; ''The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner.''; PubMedEurope PMCScholia
Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K.; ''Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop.''; PubMedEurope PMCScholia
Araki S, Ito M, Kureishi Y, Feng J, Machida H, Isaka N, Amano M, Kaibuchi K, Hartshorne DJ, Nakano T.; ''Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase.''; PubMedEurope PMCScholia
Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM.; ''The semaphorin 4D receptor controls invasive growth by coupling with Met.''; PubMedEurope PMCScholia
Halloran MC, Wolman MA.; ''Repulsion or adhesion: receptors make the call.''; PubMedEurope PMCScholia
Oinuma I, Katoh H, Negishi M.; ''Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity.''; PubMedEurope PMCScholia
Ahmed A, Eickholt BJ.; ''Intracellular kinases in semaphorin signaling.''; PubMedEurope PMCScholia
Hirotani M, Ohoka Y, Yamamoto T, Nirasawa H, Furuyama T, Kogo M, Matsuya T, Inagaki S.; ''Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors.''; PubMedEurope PMCScholia
Zhou Y, Gunput RA, Pasterkamp RJ.; ''Semaphorin signaling: progress made and promises ahead.''; PubMedEurope PMCScholia
Watanabe T, Hosoya H, Yonemura S.; ''Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells.''; PubMedEurope PMCScholia
Sasaki Y, Cheng C, Uchida Y, Nakajima O, Ohshima T, Yagi T, Taniguchi M, Nakayama T, Kishida R, Kudo Y, Ohno S, Nakamura F, Goshima Y.; ''Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex.''; PubMedEurope PMCScholia
Chong C, Tan L, Lim L, Manser E.; ''The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity.''; PubMedEurope PMCScholia
Sturdivant JM, Royalty SM, Lin CW, Moore LA, Yingling JD, Laethem CL, Sherman B, Heintzelman GR, Kopczynski CC, deLong MA.; ''Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma.''; PubMedEurope PMCScholia
Ueda K, Murata-Hori M, Tatsuka M, Hosoya H.; ''Rho-kinase contributes to diphosphorylation of myosin II regulatory light chain in nonmuscle cells.''; PubMedEurope PMCScholia
Mitsui N, Inatome R, Takahashi S, Goshima Y, Yamamura H, Yanagi S.; ''Involvement of Fes/Fps tyrosine kinase in semaphorin3A signaling.''; PubMedEurope PMCScholia
Koncina E, Roth L, Gonthier B, Bagnard D.; ''Role of semaphorins during axon growth and guidance.''; PubMedEurope PMCScholia
Ito Y, Oinuma I, Katoh H, Kaibuchi K, Negishi M.; ''Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse.''; PubMedEurope PMCScholia
Pandey D, Pandey D, Goyal P, Bamburg JR, Siess W.; ''Regulation of LIM-kinase 1 and cofilin in thrombin-stimulated platelets.''; PubMedEurope PMCScholia
Ikebe M, Hartshorne DJ.; ''Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase.''; PubMedEurope PMCScholia
Deo RC, Schmidt EF, Elhabazi A, Togashi H, Burley SK, Strittmatter SM.; ''Structural bases for CRMP function in plexin-dependent semaphorin3A signaling.''; PubMedEurope PMCScholia
Schmidt EF, Strittmatter SM.; ''The CRMP family of proteins and their role in Sema3A signaling.''; PubMedEurope PMCScholia
Vikis HG, Li W, Guan KL.; ''The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding.''; PubMedEurope PMCScholia
Whitford KL, Ghosh A.; ''Plexin signaling via off-track and rho family GTPases.''; PubMedEurope PMCScholia
ROCK I (alternatively called ROK ?) and ROCK II (also known as Rho kinase or ROK ?) were originally isolated as RhoA-GTP interacting proteins. The kinase domains of ROCK I and ROCK II are 92% identical, and so far there is no evidence that they phosphorylate different substrates. RhoA, RhoB, and RhoC associate with and activate ROCK but other GTP-binding proteins can be inhibitors, e.g. RhoE, Rad and Gem. PDK1 kinase promotes ROCK I activity not through phosphorylation but by blocking RhoE association. PLK1 can phosphorylate ROCK II and this enhances the effect of RhoA. Arachidonic acid can activate ROCK independently of Rho.
Class 2 myosins are a set of protein complexes that bind actin and hydrolyse ATP, acting as molecular motors. They consist of two myosin heavy chains , two essential light chains and two regulatory light chains (MRLCs). Smooth muscle and non-muscle myosin isoforms are a subset of Class 2 myosin complexes. The nomenclature for isoforms is misleading, as non-muscle isoforms can be found in smooth muscle. The 4 smooth muscle isoforms all have heavy chains encoded by MYH11. The non-muscle isoforms have heavy chains encoded by MYH9, MYH10 or MYH14 (NMHC-IIA, B and C). The essential light chain (LC17) common to smooth and non-muscle isoforms is encoded by MYL6. The regulatory light chain (LC20) is encoded by either MYL9, giving a slightly more basic protein that is referred to as the smooth muscle LC20 isoform, and MRLC2, giving a more acidic isoform referred to as the non-muscle LC20 isoform.
Class 2 myosins play a crucial role in a variety of cellular processes, including cell migration, polarity formation, and cytokinesis.
Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including smooth muscle contraction, cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10, MYH14 (NMHC-IIA, B and C) or MYH11, two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYL12B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 (commonly referred in the literature as Thr-18 and Ser-19) increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective (Ikebe and Hartshorne 1985, Ikebe et al. 1988). Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- or diphosphorylating MRLC (Amano et al., 1996, Ueda et al., 2002, Watanabe et al. 2007).
SEMA4D also associates with CD45, a cell surface protein tyrosine phosphatase (PTP) considered a key molecule in the T-cell receptor (TCR) activation process.
In the immune system, Sema4D/CD100 binds CD72 to mediate B-cell-B-cell, B-cell-T-cell and T-cell-dendritic cell interactions and there by regulates B-cell and T-cell activation. In B-cells, this interaction directs the dissociation of SHP-1 from the CD72 cytoplasmic domain and enhances their activation.
Sema4D binds Plexin-B1 to induce repulsive or attractive effects in neuronal and nonneuronal cells. Plexins constitute a large family of transmembrane proteins that function as receptors for semaphorins and their interaction governs cell adhesion and migration in a variety of tissues. All B-class plexins can interact with the receptor tyrosine kinases Met and ErbB2. Upon binding of Sema4D to plexin-B1, the kinase activity of ErbB2 is increased resulting in tyrosine phosphorylation of both Plexin-B1 and ErbB2. ErbB2 has been shown to mediate Sema4D-induced growth cone collapse in hippocampal neurons by the activation of RhoA via plexinB1 and PDZRhoGEF/LARG. Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038) but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified.
Binding of Sema3A to the Neuropilin-1-Plexin-A receptor complex results in the recruitment of Rnd1 to the cytoplasmic linker region of Plexin-A. Rnd1 activates the cytoplasmic GTPase signaling domain of Plexin-A.
Plexin-bound Rac1 binds to and stimulates the kinase activity of PAK. PAK dimers are arranged in head-to-tail fashion, in which the catalytic domain binds the kinase inhibitory (KI) domain and is supported by associated PAK-interacting exchange factor (PIX) dimers. Upon Rac1 binding the kinase undergoes conformational change that allows autophosphorylation. Phosphorylation of serine residues disables the KI-domain-kinase interaction and thereby reduces the affinity of PIX.
PlexinA1 and A2 are constitutively bound to the src family tyrosine kinase, Fyn. Stimulation with Sema3A causes Fyn activation and leads to the recruitment of Cdk5 into the complex.
Although neuropilin-1 is required for Sema-3A action, it is incapable of transmitting a Sema-3A signal to the growth cone interior. The function of Sema-3A is mediated by Plexins. Sema-3A binds with high affinity to Plexin when the latter is complexed with Neuropilin-1. Plexin-A1 is known to act as an R-Ras GAP (GTPase activating protein) when bound by Sema-3A. Plexin's GAP activity is regulated by FARP2 mediated Rac1 activation. Sema-3A binding to neuropilin-1/Plexin-A1 seems to induce a conformational change of plexin-A1 necessary for releasing FARP2. This suggests that neuropilin1 is required not only for ligand binding, but also for signaling, by modulating the interaction of FARP2 with plexin-A1.
Sema3A binding to Neuropilin-1:Plexin-A complex results in conformational change of plexin-A and this conformational change permits Fes nonreceptor tyrosine kinase to bind and phosphorylate Plexin-A. The specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified.
Plexin-A's are GAPs for the Ras family GTPase R-Ras. On stimulation with Rnd-1, plexin-A directly and specifically down regulates R-Ras activity. R-Ras activity is critical for PI3K activation and ECM-mediated beta1 integrin activation and cell migration. Inactivation of R-Ras by Sema3A/Plexin-A1 reduces integrin-mediated adhesions. It has been suggested that the final step in the Sema3A repulsive signaling pathway is inhibition of integrin activity. Reduced integrin activity allows detachment from the substratum and subsequent cell retraction.
Sema3A also mediates integrin inhibition by a mechanism involving PIPKI gamma 661, a phosphatidylinositol kinase that participates in integrin mediated focal adhesion assembly. The binding of talin to beta-integrin is required for integrin activation and is strengthened by PtdIns(4,5)P(2). PIPKI gamma 661, an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. Sema3A induced dissociation of FARP2 from Plexin-A1 stimulates an interaction between FARP2 and PIPKI gamma 661. FARP2 inhibits PIPK gamma 661's kinase activity, and thus inhibits integrin mediated adhesion.
Sema3A-mediated dissociation of FARP2 from Plexin-A is followed by activation of Rac1 by the GEF activity of released FARP2. FARP2 is critical for Sema3A-mediated axonal repulsion through two independent downstream signaling pathways. Sema3A mediated disassociation of FARP2 from Plexin-A is followed by activation of Rac by GEF activity of released FARP2, binding of Rnd1 to plexin-A and down regulation of R-Ras by GAP activity of plexin-A.
PAK is autophosphorylated at several sites but S-144 flanking the kinase inhibitor region and T-423 (S-141/T-402 in PAK-gamma) within the catalytic domain are the two conserved sites that regulate the catalytic activity.
Active Rac1 associates directly with Plexin-A1 in the linker region separating Plexin-A1's cytoplasmic GAP domains. Rac1 association relieves an inhibitory intramolecular interaction between the two Plexin-A1 GAP domains C1 and C2.
The best characterized receptors for mediating semaphorin signaling are members of the neuropilin and plexin families of transmembrane proteins. Neuropilins form complexes with Plexin-A which in turn can act as a signaling moiety. Also, when complexed with neuropilin-1, plexin-A1 can associate directly with the FERM domain containing guanine nucleotide exchange factor (GEF) FARP2. FARP2 exerts GEF activity for Rac but not Cdc42 and Rho.
Cdk5:p35 complex is associated with Plexin-A through the actived form of Fyn. CRMPs are the downstream substrates for Cdk5. Cdk5 phosphorylates serine 522 of CRMPs. Phosphorylation of CRMPs mediates the Sema3A induced growth cone collapse. Collapsin response mediator proteins (CRMPs) are five homologous cytosolic phosphoproteins (CRMP1–5) involved in neuronal differentiation and axonal guidance. These members oligomerize and exist as tetramers.
Cyclin-dependent kinase 5 (CDK5), a member of the serine/threonine kinase Cdk family, is complexed with p35 a neuron specific activator of Cdk5. The complex CDK5:p35 is required for neurite outgrowth and cortical lamination. CDK5:p35 complex is recruited to the growth cone by associating with active Fyn. FYN promotes the kinase activity of CDK5 by phosphorylating CDK5 on tyrosine residue 15. Activation of CDK5 by FYN via Tyr15 phosphorylation might facilitate suppression of RAC-PAK signaling downstream of PlexinA.
Fes bound to Plexin-A is able to phosphorylate all five forms of CRMP, though neither specific sites nor the consequence of tyrosine phosphorylation in CRMP's have yet been investigated directly.
The EPHB2-FAK pathway partially promotes dendritic spine stability through LIMK-mediated cofilin (CFL1) phosphorylation (Shi et al. 2009). CFL1 is a member of the ADF (actin-depolymerizing factor) protein family that is involved in regulating actin dynamics in the growth cone. It binds to actin in a one-to-one molar ratio, and stimulates both the severing of actin filaments and depolymerization of actin subunits from the actin filament end. Activated LIMK phosphorylates CFL1 on the conserved serine 3 residue located near the actin-binding site. After phosphorylation, CFL1 is inactive, loses its affinity for actin and dissociates from G-actin monomers. Once freed, ADP-actin monomers can exchange ADP with cytoplasmic ATP, ready for reincorporation at the barbed end of a growing filament (Gungabissoon & Bamburg 2003).
The phosphorylation of CRMPs at Ser522 allows the subsequent phosphorylation of CRMP1, CRMP2 and CRMP4 at Ser518, Thr509, and Thr514 mediated by serine/threonine kinase GSK3beta. Phosphorylation of CRMP by GSK3beta results in decreased CRMP affinity for beta-tubulin and changes in microtubule dynamics.
LIM kinases are serine protein kinases with a unique combination of two N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. LIMK1 is one of the downstream targets of PAK1 and is activated through phosphorylation by PAK1 on T508 within its activation loop (Edwards et al. 1999, Aizawa et al. 2001). LIM-kinase is responsible for the tight regulation of the activity of cofilin (a protein that depolymerizes actin filaments) and thus maintains the balance between actin assembly and disassembly. Phosphorylated cofilin is inactive, resulting in stabilization of the actin cytoskeleton.
Rnd1 is constitutively active and stably associates with Plexin-B1 and regulates the R-Ras GAP activity of the C1 and C2 domains of the Plexin-B1 cytoplasmic tail. These domains interact with each other and in this closed conformation cannot associate with active R-Ras-GTP. Rnd1 binds to the region between C1 and C2 domains and disrupts this interaction, allowing the receptor to associate with GTP-bound R-Ras.
The cytoplasmic tails of plexins have two domains, C1 and C2, which are highly conserved and act as GAP for small GTPases like Rac1. Active Rac1 binds directly to a binding domain of Plexin-B1 in the linker region between C1 and C2. The functional consequence of the plexin-B1/Rac interaction is not understood but this binding might sequester Rac1 away from p21-activated kinase (PAK). Plexin-B1 can compete with PAK for binding to active Rac and this competition results in the ability of plexin-B1 to inhibit Rac-induced PAK activation.
Plexin-B1 functions as an R-Ras GTPase-activating protein (GAP) and directly and specifically down regulates R-Ras activity in response to Sema4D, inducing growth cone collapse. R-Ras inactivation promotes PI3K and Akt inactivation followed by GSK-3beta activation and CRMP inactivation. R-Ras inactivation also inhibits cell migration by regulating beta1 integrin activity.
p190RhoGAP complexed with Plexin-B1 stimulates GTP hydrolysis by RhoA. The resulting lower levels of Rho-GTP may account for F-actin depolymerization and cytoskeletal rearrangements.
Plexin-B1 activates RhoA and induces growth cone collapse and and cytoskeletal reorganization through Rho-specific guanine nucleotide exchange factors PDZ-RhoGEF (ARHGEF11) and leukemia-associated RhoGEF (LARG, ARHGEF12). Plexin-B1 directly interacts with PDZ-RhoGEF through its c-terminal PDZ domain binding motif. It has been suggested that Rnd1, which binds to the cytoplasmic part of plexin-B1, can promote the interaction between plexin-B1 and PDZ-RhoGEF. The PDZ domain of LARG is directly involved in the interaction with the c-terminal sequence of Plexin-B1.
SEMA3E binds to neither neuropilin but instead binds directly to plexin-D1. This interaction controls endothelial cell positioning and the patterning of the developing vasculature.
Sema4A binds plexinD1 to inhibit angiogenesis. Sema4A–plexinD1 interactions modulate VEGF-mediated endothelial cell migration and proliferation at the intracellular level by suppressing VEGF–VEGFR2-induced activation of Rac1, Akt and integrins.
Sema5s have been implicated in invasive growth, vascular patterning and axon guidance. Plexin-B3 is the specific and high-affinity receptor for Sema5A, and their interaction triggers the collapsing response.
Plexin-A1 is a receptor for the transmembrane semaphorin, Sema6D. Plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12.
ROCKs are primarily known as downstream effectors of RHO, but they can also be activated by arachidonic acid, which binds to the pleckstrin homology domain, releasing an autoinhibitory loop within ROCK and allowing catalytic activity (Araki et al. 2001). Proteolytic cleavage at the C-terminus by caspase-3 and granzyme B also activates ROCK1 and ROCK2, causing plasma membrane blebbing during apoptosis (Coleman et al. 2001, Sebbagh et al. 2005). Multiple targets of ROCK contribute to the stabilization of actin filaments and the generation of actin-myosin contractile force.
LIM kinases are serine protein kinases with a unique combination of two N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. ROCK1 and ROCK2 phosphorylate and activate LIM kinases LIMK1 and LIMK2 at Thr508 and Thr505, respectively (Ohashi et al. 2000, Sumi et al. 2001). These threonine residues lay within the activation loop of the kinase domain. LIMKs phosphorylate and inactivate cofilin, an actin depolymerizing factor, resulting in stabilization of the actin cytoskeleton (Pandey et al. 2006).
Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including smooth muscle contraction, cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10, MYH14 (NMHC-IIA, B and C) or MYH11, two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYL12B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 (commonly referred in the literature as Thr-18 and Ser-19) increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective (Ikebe and Hartshorne 1985, Ikebe et al. 1988). Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- or diphosphorylating MRLC (Amano et al., 1996, Ueda et al., 2002, Watanabe et al. 2007).
Binding of Hsp90 to the LIMK proteins protects them from degradation and promotes their dimer formation and transphosphorylation. It is estimated that LIMK1 contains at least 5 phospho-amino acids primarily phospho-serines, in its kinase domain. The positions of these serine residues are not known. Transphosphorylation of these serine residues in LIMK1 increases its stability.
After phosphorylation on Thr 508, LIMK undergoes homodimerization. Homodimer formation is promoted by the binding of heat shock protein 90 (Hsp90) to a short sequence in the kinase domain of LIMKs. LIMKs are further phosphorylated after homodimer formation and transphosphorylation of the kinase domain.
Sema4D binds Plexin-B1 to induce repulsive or attractive effects in neuronal and nonneuronal cells. Plexins constitute a large family of transmembrane proteins that function as receptors for semaphorins and their interaction governs cell adhesion and migration in a variety of tissues. All B-class plexins can interact with the receptor tyrosine kinases Met and ErbB2. The binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of Met, leading to the phosphorylation of both Plexin-B1 and Met. The phosphorylation of the plexin-B1/Met complex induced by Sema4D is crucial for epithelial cell migration and invasive growth. Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038), but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified.
Sema7A signals through two unrelated receptors, an RGD-dependent alpha1beta1-integrin and a member of the plexin family, plexinC1. Sema7A-plexinC1 interactions have been implicated in immune system function and also participate in neuronal network formation.
Sema7A has a RGD-motif in the extracellular region and interacts with alpha1beta1 integrin in both olfactory nerves and monocytes/macrophages. This interaction stimulates cytokine production in monocytes and macrophages, and is critical for the effector phase of the inflammatory immune response.
Ripasudil (Glanatec), as its hydrochloride hydrate (K-115), is a specifc Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor (ROCKi) used for the treatment of glaucoma and ocular hypertension in Japan (Garnock-Jones 2014). Netarsudil is a USA-approved ROCKi used to treat glaucoma and ocular hypertenstion (Sturdivant et al. 2016, Tanna & Johnson 2018).
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myosin IIAnnotated Interactions
Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038) but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified.
Plexin-A1 is known to act as an R-Ras GAP (GTPase activating protein) when bound by Sema-3A. Plexin's GAP activity is regulated by FARP2 mediated Rac1 activation. Sema-3A binding to neuropilin-1/Plexin-A1 seems to induce a conformational change of plexin-A1 necessary for releasing FARP2. This suggests that neuropilin1 is required not only for ligand binding, but also for signaling, by modulating the interaction of FARP2 with plexin-A1.
FARP2 is critical for Sema3A-mediated axonal repulsion through two independent downstream signaling pathways. Sema3A mediated disassociation of FARP2 from Plexin-A is followed by activation of Rac by GEF activity of released FARP2, binding of Rnd1 to plexin-A and down regulation of R-Ras by GAP activity of plexin-A.
Collapsin response mediator proteins (CRMPs) are five homologous cytosolic phosphoproteins (CRMP1–5) involved in neuronal differentiation and axonal guidance. These members oligomerize and exist as tetramers.
muscle/non-muscle
myosin II