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

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ArcPathVisio Brace Ellipse EndoplasmicReticulum GolgiApparatus HexagonPathVisio MimDegradation Mitochondria Octagon PentagonPathVisio Rectangle RoundedRectangle SarcoplasmicReticulum TriangleEquilateralEast TrianglePathVisio none +pMitochondriaMilk proteins-p+pProliferationMAPK signalingGap junctionNFKBDifferentiationORAI1ERBB2CCND1PGRYY1PRLGALTTC9EstrogenTPM3BCL2L1TNFSF11EGFREIF4EMYCPNCKPTPN1EGFRELF5CHUKCAV1CCND1ESR2JAK2GJB2USF1ERBB4NRG1ERBB3CSN2ESR1USF2CEBPAOxytocinBCL2L1EIF4G1CEBPBATP2C2NR3C1TNFRSF11ANFIANFICNFIBNFIXMAPK1MAPK8MAPK10MAPK12MAPK14MAPK3MAPK9MAPK11MAPK13+pGALPRLRProgesteronePubertyMammary gland development pathwayInvolutionPregnancy and lactationEmbryonic developmentInvolutionCEBPACEBPBSTAT5ASTAT5BPI3WFDC5SLPIWFDC2WFDC8WFDC11NFKB1RELANFKB2RELBRELSTAT5ASTAT5BNFIMAPKName: Mammary gland development: pregnancy and lactation - stage 3 of 4Organism: Homo sapiens


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 (EGFR aka 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](https://www.ncbi.nlm.nih.gov/pubmed/16231422). 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](https://www.ncbi.nlm.nih.gov/pubmed/16231422). CEBPA and CEBPB are related to the balance between proliferation and differentiation of epithelial cells [2](https://www.ncbi.nlm.nih.gov/pubmed/9513715). The TNFSF11/ TNFRSF11A pathway is associated with proliferation [1](https://www.ncbi.nlm.nih.gov/pubmed/16231422). MYC, galanin and PTPN1 are regulators of the JAK2/STAT5 pathway and UFS are implicated in cell cycle control [1](https://www.ncbi.nlm.nih.gov/pubmed/16231422) [3](https://www.ncbi.nlm.nih.gov/pubmed/15689376) [4](http://www.ncbi.nlm.nih.gov/pubmed/12907752) [5](https://www.ncbi.nlm.nih.gov/pubmed/23154416). 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](https://www.ncbi.nlm.nih.gov/pubmed/16231422). ERBB4 substitutes JAK2 by phosphorylating STAT5. Finally, in the last two cases, estrogen binds to its receptors, ESR1 and ESR2, and stimulates PGR [1](https://www.ncbi.nlm.nih.gov/pubmed/16231422). 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](https://www.ncbi.nlm.nih.gov/pubmed/22917536).

PNCK appears to negatively regulate EGFR and MAPK signaling during pregnancy [7](https://www.ncbi.nlm.nih.gov/pubmed/18562482). 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](https://www.ncbi.nlm.nih.gov/pubmed/23840669).

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Quality Tags

Image:Curated.pngApproved version
Image:MissingXref.pngAnnotate nodes

Ontology Terms

 

Bibliography

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  1. 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
  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. 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
  4. 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
  5. Hennighausen L, Robinson GW; ''Information networks in the mammary gland.''; Nat Rev Mol Cell Biol, 2005 PubMed Europe PMC Scholia
  6. 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
  7. 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
  8. 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

History

View all...
CompareRevisionActionTimeUserComment
138147
Approved
view11:03, 18 March 2025EweitzModified description
138146view11:02, 18 March 2025EweitzUse gene symbols
138017view12:50, 11 March 2025EweitzModified description
138016view12:49, 11 March 2025EweitzModified description
138015view12:49, 11 March 2025EweitzModified description
136692view22:56, 19 February 2025EweitzEconomize layout
136533view01:47, 6 February 2025EweitzClear dimension cache
136532view01:47, 6 February 2025EweitzShorten rightmost interaction
136531view01:38, 6 February 2025EweitzEvenly space branch points
136530view01:33, 6 February 2025EweitzAlign nodes
136529view01:32, 6 February 2025EweitzClear dimension cache
136528view01:30, 6 February 2025EweitzEconomize layout
136527view01:23, 6 February 2025EweitzAdjust
136526view01:21, 6 February 2025EweitzAdjust
136525view01:20, 6 February 2025EweitzTry changing end X
136524view01:19, 6 February 2025EweitzTry aligning phases
136523view01:18, 6 February 2025EweitzSeparate lines
136522view01:17, 6 February 2025EweitzDiscrepancy seems unresolvable, oddly
136521view01:15, 6 February 2025EweitzAdjust
136520view01:15, 6 February 2025EweitzAdjust per discrepancy
136519view01:14, 6 February 2025EweitzAdjust per Kaavio / PathVisio discrepancy
136518view01:14, 6 February 2025EweitzWiden node
136517view01:13, 6 February 2025EweitzEconomize layout
136516view01:05, 6 February 2025EweitzWiden truncated node
136515view01:04, 6 February 2025EweitzAlign nodes
136514view01:02, 6 February 2025EweitzWiden nodes
136513view00:59, 6 February 2025EweitzIncrease font size
136512view00:52, 6 February 2025EweitzIncrease font size
136511view00:50, 6 February 2025EweitzFix +p / -p positions
135754view02:19, 9 November 2024EweitzFix PathVisio / Kaavio discrepancy with "double" line style
135753view02:17, 9 November 2024EweitzExpand MAPK gene family
135752view02:01, 9 November 2024EweitzRefine NFKB modeling as complex, not merely group
135751view01:57, 9 November 2024EweitzUse gene symbol
135750view01:52, 9 November 2024EweitzExpand NFI gene family
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

External references

DataNodes

View all...
Name  ↓Type  ↓Database reference  ↓Comment  ↓
ATP2C2GeneProductENSG00000064270 (Ensembl)
BCL2L1GeneProductENSG00000171552 (Ensembl)
CAV1GeneProductENSG00000105974 (Ensembl)
CCND1GeneProductENSG00000110092 (Ensembl)
CEBPAGeneProductENSG00000245848 (Ensembl)
CEBPBGeneProductENSG00000172216 (Ensembl)
CHUKGeneProductENSG00000213341 (Ensembl) "IKKA" originally
CSN2GeneProductENSG00000135222 (Ensembl)
EGFRGeneProduct1956 (Entrez Gene) "ERBB1" originally
EGFRGeneProductENSG00000146648 (Ensembl)
EIF4EGeneProductENSG00000151247 (Ensembl)
EIF4G1GeneProductENSG00000114867 (Ensembl)
ELF5GeneProductENSG00000135374 (Ensembl)
ERBB2GeneProductENSG00000141736 (Ensembl)
ERBB3GeneProductENSG00000065361 (Ensembl)
ERBB4GeneProductENSG00000178568 (Ensembl)
ESR1GeneProductENSG00000091831 (Ensembl)
ESR2GeneProductENSG00000140009 (Ensembl)
Embryonic developmentPathwayWP2813 (WikiPathways)
EstrogenMetaboliteCHEBI:4903 (ChEBI)
GALGeneProduct51083 (Entrez Gene) "Galanin" originally
GJB2GeneProductENSG00000165474 (Ensembl)
InvolutionPathwayWP2815 (WikiPathways)
JAK2GeneProductENSG00000096968 (Ensembl)
MAPK10GeneProductENSG00000118273 (Ensembl)
MAPK11GeneProductENSG00000135846 (Ensembl)
MAPK12GeneProductENSG00000169286 (Ensembl)
MAPK13GeneProductENSG00000080845 (Ensembl)
MAPK14GeneProductENSG00000134725 (Ensembl)
MAPK1GeneProductENSG00000122968 (Ensembl)
MAPK2.7.11.24 (Enzyme Nomenclature)
MAPK3GeneProductENSG00000168247 (Ensembl)
MAPK8GeneProductENSG00000117687 (Ensembl)
MAPK9GeneProductENSG00000167674 (Ensembl)
MYCGeneProductENSG00000136997 (Ensembl)
NFIAGeneProductENSG00000162599 (Ensembl)
NFIBGeneProductENSG00000147862 (Ensembl)
NFICGeneProductENSG00000141905 (Ensembl)
NFIXGeneProductENSG00000008441 (Ensembl)
NFKB1GeneProductENSG00000114515 (Ensembl)
NFKB2GeneProductENSG00000114526 (Ensembl)
NR3C1GeneProductENSG00000113580 (Ensembl)
NRG1GeneProductENSG00000157168 (Ensembl)
ORAI1GeneProductENSG00000276045 (Ensembl)
OxytocinMetaboliteQ169960 (Wikidata)
PGRGeneProductENSG00000082175 (Ensembl)
PI3GeneProductENSG00000170328 (Ensembl)
PNCKGeneProductENSG00000130822 (Ensembl)
PRLGeneProduct5617 (Entrez Gene)
PRLRGeneProductENSG00000113494 (Ensembl)
PTPN1GeneProductENSG00000196396 (Ensembl)
Pregnancy and lactationPathwayWP2817 (WikiPathways)
ProgesteroneMetaboliteCHEBI:17026 (ChEBI)
PubertyPathwayWP2814 (WikiPathways)
RELAGeneProductENSG00000184697 (Ensembl)
RELBGeneProductENSG00000103171 (Ensembl)
RELGeneProductENSG00000105825 (Ensembl)
SLPIGeneProductENSG00000130328 (Ensembl)
STAT5AGeneProductENSG00000126561 (Ensembl)
STAT5BGeneProductENSG00000173757 (Ensembl)
TNFRSF11AGeneProductENSG00000141655 (Ensembl)
TNFSF11GeneProductENSG00000120659 (Ensembl)
TPM3GeneProductENSG00000143549 (Ensembl)
TTC9GeneProductENSG00000133985 (Ensembl)
USF1GeneProductENSG00000158773 (Ensembl)
USF2GeneProductENSG00000105698 (Ensembl)
WFDC11GeneProductENSG00000171504 (Ensembl)
WFDC2GeneProductENSG00000170992 (Ensembl)
WFDC5GeneProductENSG00000109316 (Ensembl)
WFDC8GeneProductENSG00000167630 (Ensembl)
YY1GeneProductENSG00000100811 (Ensembl)

Annotated Interactions

No annotated interactions

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