Mammary gland development: pregnancy and lactation - stage 3 of 4 (Homo sapiens)

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54181788886882183888888783628688888815868888881811PubertyMAMMARY GLAND DEVELOPMENTPATHWAYMAPK SignalingGap junctionProliferation-pMilk proteins+pDifferentiation+pMitochondriaInvolutionATP2C2CCND1TNFRSF11ABCL2L1CEBPTNFSF11MAPKSTAT5ELF5CEBPACEBPBTPM3WFDCUSFBCL2L1DNAPRLPTPN1ERBB4IKKAYY1GJB2CAV1STAT5EstrogenMYCJAK2NFIUSF2CSN2ESR1CCND1ERBB1ORAI1PNCKNFKBERBB3TTC9NRGoxytocinEIF4EGalaninPGRERBB2NR3C1EGFRESR2EIF4G1+pPregnancy and lactationEmbryonic developmentInvolutionGalaninPRLRPROGESTERONEDNADNADNADNADNADNA


Description

The secondary mammary gland can be inactive or active. It becomes active during pregnancy and lactation, when there is a formation of alveoli, the structure responsible for milk production.

There are four signal inputs for the mammary gland development during pregnancy and lactation: (1) prolactin receptor (PRLR), (2) epidermal growth factor receptors (ERBB1, ERBB2, ERBB3 and ERBB4), (3) estrogen receptors (ESR1 and ESR2) and (4) progesterone receptor (PGR). In the first case, PRL binds to PRLR, allowing its phosphorylation by JAK2, and the consequent coupling of STAT5 1. JAK2 phosphorylates STAT5, allowing its migration to nucleus. STAT5 target genes are related to proliferation (TNFSF11, CCND1), differentiation (CSN2, WFDC, ELF5, GJB2) and survival (BCL2L1) 1. CEBPA and CEBPB are related to the balance between proliferation and differentiation of epithelial cells 2. The TNFSF11/ TNFRSF11A pathway is associated with proliferation 1. MYC, galanin and PTPN1 are regulators of the JAK2/STAT5 pathway and UFS are implicated in cell cycle control 1 3 4 5. In the second case, NRG binds to one of its receptors (ERBB1, ERBB2, ERBB3 or ERBB4) and the signal is transmitted by ERBB4 to STAT5, from where it follows as described above 1. ERBB4 substitutes JAK2 by phosphorylating STAT5. Finally, in the last two cases, estrogen binds to its receptors, ESR1 and ESR2, and stimulates PGR 1. ESR1, ESR2 and PGR are associated with proliferation. ESR1 also affects adhesion through induction of TTC9, which interacts with TPM3 (a protein associated with actin filaments), playing a role in involution 6.

PNCK appears to negatively regulate EGFR and MAPK signaling during pregnancy 7. ATP2C2 is co-expressed with the component of Calcium influx channel encoded by ORAI1. Together, they regulate Ca2+ uptake, influencing differentiation and supporting the large calcium transport requirements for milk secretion during lactation 8.

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Bibliography

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  1. Rosen JM, Zahnow C, Kazansky A, Raught B; ''Composite response elements mediate hormonal and developmental regulation of milk protein gene expression.''; Biochem Soc Symp, 1998 PubMed Europe PMC Scholia
  2. Cross BM, Hack A, Reinhardt TA, Rao R; ''SPCA2 regulates Orai1 trafficking and store independent Ca2+ entry in a model of lactation.''; PLoS One, 2013 PubMed Europe PMC Scholia
  3. Deb TB, Coticchia CM, Barndt R, Zuo H, Dickson RB, Johnson MD; ''Pregnancy-upregulated nonubiquitous calmodulin kinase induces ligand-independent EGFR degradation.''; Am J Physiol Cell Physiol, 2008 PubMed Europe PMC Scholia
  4. Hadsell DL, Bonnette S, George J, Torres D, Klimentidis Y, Gao S, Haney PM, Summy-Long J, Soloff MS, Parlow AF, Sirito M, Sawadogo M; ''Diminished milk synthesis in upstream stimulatory factor 2 null mice is associated with decreased circulating oxytocin and decreased mammary gland expression of eukaryotic initiation factors 4E and 4G.''; Mol Endocrinol, 2003 PubMed Europe PMC Scholia
  5. Blakely CM, Sintasath L, D'Cruz CM, Hahn KT, Dugan KD, Belka GK, Chodosh LA; ''Developmental stage determines the effects of MYC in the mammary epithelium.''; Development, 2005 PubMed Europe PMC Scholia
  6. Hennighausen L, Robinson GW; ''Information networks in the mammary gland.''; Nat Rev Mol Cell Biol, 2005 PubMed Europe PMC Scholia
  7. Milani ES, Brinkhaus H, Dueggeli R, Klebba I, Mueller U, Stadler M, Kohler H, Smalley MJ, Bentires-Alj M; ''Protein tyrosine phosphatase 1B restrains mammary alveologenesis and secretory differentiation.''; Development, 2013 PubMed Europe PMC Scholia
  8. Shrestha S, Cao S, Lin VC; ''The local microenvironment instigates the regulation of mammary tetratricopeptide repeat domain 9A during lactation and involution through local regulation of the activity of estrogen receptor α.''; Biochem Biophys Res Commun, 2012 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
135715view11:37, 30 October 2024EweitzRefine interaction position
135677view03:42, 22 October 2024EweitzRefine position
135676view03:41, 22 October 2024EweitzUse gene symbols, simplification interactions
135675view03:38, 22 October 2024EweitzRefine positioning
135674view03:37, 22 October 2024EweitzRefine positioning
135673view03:36, 22 October 2024EweitzExpand NFKB gene family
135672view03:16, 22 October 2024EweitzExpand WFDC gene family
135666view02:36, 21 October 2024EweitzUse simpler, more specific interactions; use gene symbols
134256view04:59, 18 July 2024EgonwRemoved template comments
129080view14:39, 10 March 2024EweitzModified title
128957view14:48, 25 February 2024EgonwRemoved an unconnected datanode without label
128683view15:49, 19 February 2024EweitzFix slight left-truncation of "Gap junction" only seen in site rendering
128682view15:30, 19 February 2024EweitzUpgrade "Involution" to pathway
128681view15:26, 19 February 2024EweitzUntangle interaction
128680view15:23, 19 February 2024EweitzEconomize layout
128679view15:10, 19 February 2024EweitzFix mitochondria graphics discrepancy, economize layout, standardize case
128678view15:01, 19 February 2024EweitzEconomize layout
128677view14:50, 19 February 2024EweitzExperiment with clickable pathway containing other nodes; use site-visible lines for cell membrane
128670view13:25, 19 February 2024EweitzUpdate top nodes
128668view13:17, 19 February 2024EweitzUpdate top nodes
123894view10:55, 25 August 2022FinterlyReverted to version '07:17, 18 August 2022' by Finterly
123893view10:27, 25 August 2022Finterlyremoved CellularComponent "None"
123849view07:17, 18 August 2022Mkutmonfix special shape
102410view20:05, 22 December 2018EgonwReplaced another secondary ChEBI ID with primary ID.
102409view20:03, 22 December 2018EgonwReplaced a secondary ChEBI ID with primary ID.
102398view14:14, 22 December 2018DeSlUpdated layout; connected unconnected lines; changes vertical lines to graphical iso interaction.
102397view14:10, 22 December 2018DeSlAdded ID for EIF4G
102396view14:08, 22 December 2018DeSlAnnotated middle and right side.
102395view13:49, 22 December 2018DeSlANnotated left bottom part
102394view13:42, 22 December 2018DeSlAnnotated left hand side with IDs.
88703view16:18, 12 August 2016JmeliusOntology Term : 'regulatory pathway' added !
77101view22:03, 17 July 2014KhanspersOntology Term : 'milk secreting cell' added !
75456view18:52, 30 May 2014BiodadosModified description
75455view18:48, 30 May 2014Biodados
75454view18:46, 30 May 2014BiodadosPeriodical save, work in progress
75453view18:43, 30 May 2014Biodados
75452view18:41, 30 May 2014Biodados
75451view18:37, 30 May 2014Biodados
75450view18:36, 30 May 2014BiodadosPeriodical save, work in progress
75449view18:33, 30 May 2014Biodados
75448view18:31, 30 May 2014Biodados
75447view18:23, 30 May 2014BiodadosPeriodical save, work in progress
75446view18:10, 30 May 2014BiodadosPeriodical save, work in progress
75445view17:47, 30 May 2014Biodados
75444view17:29, 30 May 2014Biodados
75443view17:16, 30 May 2014BiodadosModified description
75442view16:44, 30 May 2014BiodadosNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ATP2C2GeneProductENSG00000064270 (Ensembl)
BCL2L1GeneProductENSG00000171552 (Ensembl)
CAV1GeneProductENSG00000105974 (Ensembl)
CCND1GeneProductENSG00000110092 (Ensembl)
CEBPGeneProduct
CEBPAGeneProductENSG00000245848 (Ensembl)
CEBPBGeneProductENSG00000172216 (Ensembl)
CSN2GeneProductENSG00000135222 (Ensembl)
DNAMetaboliteCHEBI:33698 (ChEBI)
EGFRGeneProductENSG00000146648 (Ensembl)
EIF4EGeneProductENSG00000151247 (Ensembl)
EIF4GGeneProductIPR036211 (InterPro)
ELF5GeneProductENSG00000135374 (Ensembl)
ERBB1GeneProduct1956 (Entrez Gene)
ERBB2GeneProductENSG00000141736 (Ensembl)
ERBB3GeneProductENSG00000065361 (Ensembl)
ERBB4GeneProductENSG00000178568 (Ensembl)
ESR1GeneProductENSG00000091831 (Ensembl)
ESR2GeneProductENSG00000140009 (Ensembl)
EstrogenMetaboliteCHEBI:4903 (ChEBI)
GJB2GeneProductENSG00000165474 (Ensembl)
GalaninGeneProduct51083 (Entrez Gene)
IKKAGeneProduct1147 (Entrez Gene)
JAK2GeneProductENSG00000096968 (Ensembl)
MAPKGeneProduct2.7.11.24 (Enzyme Nomenclature)
MYCGeneProductENSG00000136997 (Ensembl)
NFIGeneProduct
NFKBGeneProduct
NR3C1GeneProductENSG00000113580 (Ensembl)
NRGGeneProduct
ORAI1GeneProductENSG00000276045 (Ensembl)
PGRGeneProductENSG00000082175 (Ensembl)
PNCKGeneProductENSG00000130822 (Ensembl)
PRLGeneProduct5617 (Entrez Gene)
PRLRGeneProductENSG00000113494 (Ensembl)
PROGESTERONEMetaboliteCHEBI:45786 (ChEBI)
PTPN1GeneProductENSG00000196396 (Ensembl)
STAT5GeneProductIPR035858 (InterPro)
TNFRSF11AGeneProductENSG00000141655 (Ensembl)
TNFSF11GeneProductENSG00000120659 (Ensembl)
TPM3GeneProductENSG00000143549 (Ensembl)
TTC9GeneProductENSG00000133985 (Ensembl)
USFGeneProduct
USF2GeneProductENSG00000105698 (Ensembl)
WFDCGeneProduct
YY1GeneProductENSG00000100811 (Ensembl)
oxytocinMetaboliteQ169960 (Wikidata)

Annotated Interactions

No annotated interactions

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