Mammary gland development pathway - Pregnancy and lactation (Stage 3 of 4) (Homo sapiens)

From WikiPathways

Jump to: navigation, search
83188688188878881838888852188688168188788868288541PubertyMAMMARY GLAND DEVELOPMENTPATHWAYMAPK SignalingDifferentiation+p-pMilk proteinsProliferation+pInvolutionGap junctionMitochondriaORAI1CEBPACEBPERBB1DNAUSFNRGTNFSF11MAPKBCL2L1ERBB4ESR1MYCERBB3EstrogenPRLUSF2YY1PTPN1CSN2TPM3NR3C1ESR2ATP2C2GJB2STAT5IKKANFICCND1EIF4ECAV1CEBPBNFKBTTC9JAK2BCL2L1PNCKELF5WFDCGalaninPGRERBB2EIF4GCCND1EGFRTNFRSF11AoxytocinSTAT51+pPregnancy and lactationEmbryonic developmentInvolutionGalaninPRLRPROGESTERONEDNADNADNADNADNADNA


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.

Quality Tags

Ontology Terms



View all...
  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
  2. 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
  3. 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
  4. 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
  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
  6. 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
  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
  8. Hennighausen L, Robinson GW; ''Information networks in the mammary gland.''; Nat Rev Mol Cell Biol, 2005 PubMed Europe PMC


View all...
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


View all...
NameTypeDatabase referenceComment
ATP2C2GeneProductENSG00000064270 (Ensembl)
BCL2L1GeneProductENSG00000171552 (Ensembl)
CAV1GeneProductENSG00000105974 (Ensembl)
CCND1GeneProductENSG00000110092 (Ensembl)
CEBPAGeneProductENSG00000245848 (Ensembl)
CEBPBGeneProductENSG00000172216 (Ensembl)
CSN2GeneProductENSG00000135222 (Ensembl)
DNAMetaboliteCHEBI:16991 (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)
NR3C1GeneProductENSG00000113580 (Ensembl)
ORAI1GeneProductENSG00000276045 (Ensembl)
PGRGeneProductENSG00000082175 (Ensembl)
PNCKGeneProductENSG00000130822 (Ensembl)
PRLGeneProduct5617 (Entrez Gene)
PRLRGeneProductENSG00000113494 (Ensembl)
PTPN1GeneProductENSG00000196396 (Ensembl)
STAT5GeneProductIPR035858 (InterPro)
TNFRSF11AGeneProductENSG00000141655 (Ensembl)
TNFSF11GeneProductENSG00000120659 (Ensembl)
TPM3GeneProductENSG00000143549 (Ensembl)
TTC9GeneProductENSG00000133985 (Ensembl)
USF2GeneProductENSG00000105698 (Ensembl)
YY1GeneProductENSG00000100811 (Ensembl)
oxytocinMetaboliteQ169960 (Wikidata)

Annotated Interactions

No annotated interactions

Personal tools