Prolactin Signaling Pathway (Homo sapiens)

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Prolactin (PRL), a pleiotropic polypeptide hormone, mostly secreted by the lactotrophic cells of anterior pituitary gland and to a lesser extent expressed in numerous extra pituitary tissues such as adipose tissue, lymphocytes, blood, plasma, skin fibroblasts, mammary epithelial cells, spleen, thymus, breast, prostate and sweat glands. Prolactin has been established to be present in all vertebrates and involved in more than 300 different effects, which can be ascribed to six broad categories: (i) reproduction and lactation, (ii) growth and development, (iii) endocrinology and metabolism, (iv) brain and behaviour, (v) immunomodulation and (vi) osmoregulation. Prolactin mediates its multiple functions through prolactin receptor (PRLR), a member of class I cytokine receptor superfamily. The PRLR comprises of an extracellular ligand binding domain, a transmembrane domain and an intracellular domain. PRLR is expressed in a wide variety of tissues such as brain, mammary epithelium, liver, cerebellum and lymphocytes. Prolactin has been shown to be involved in the progression of different forms of cancer such as breast cancer and prostate cancer. Clinically, higher levels are found in patients with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Reiter’s syndrome and Sjogren’s syndrome. Besides 23 kDa full length PRL, a 16-kDa (16K PRL) N terminal fragment of prolactin produced by the cleavage by Cathepsin D has potent antiangiogenic and vasoconstrictive role in endothelial cells. In rat pulmonary fibroblasts cells 16K PRL is found to activate NF-kB pathway. Evidences also suggested that it has definite roles in programmed cell death in endothelial cells by activating various caspases. Prolactin associates with PRLR and induces the dimerization and activation of the receptor. The signaling reactions downstream of the long receptor isoform have been studied well and little is known about prolactin actions facilitated by short isoform. Since PRLR lacks intrinsic tyrosine kinase activity, it initiates signal transduction through its associated kinases in the cytoplasmic tail. PRL signaling activate Janus kinase 2 (JAK2), mitogen activated protein kinase (MAPK), Phosphoinositide 3-kinase (PI3- kinase), Src kinase and serine/threonine kinase Nek3-vav2-Rac1 pathways through the long isoform of the receptor. The prolactin signaling through short isoform can activate different downstream cascades except JAK/STAT pathway. JAK2 phosphorylates multiple tyrosine residues of the receptor PRLR and enables the binding of downstream signaling molecules mainly signal transducer and activator of transcription (STAT) proteins. The STATs are considered as major effectors for PRL-dependent cell proliferation and gene activation, with STAT5 serving as the primary mediators. The phosphorylated STAT proteins dimmerize, translocate to the nucleus, and bind to specific DNA sequences in the promoters of PRL-induced genes, activating gene transcription. Prolactin signaling also activates MAP kinase pathways and is reported to be involved in proliferation of normal and mammary tumor cells. Prolactin also stimulates PI-3K pathway and is reported that activation of PI-3K/AKT pathway initiates cell survival of lymphoid cells. Upon prolactin stimulation, the adapter protein GAB2 phosphorylated at the tyrosine residue recruits the catalytic subunit of PI-3K. Apart from these, prolactin also regulates cytoskeletal re-organization through the activation of Rac pathway. The Prolactin receptor dependent interactions of serine/threonine kinases NEK3 with guanine nucleotide exchange factors VAV1 and VAV2 and Tec with VAV1 regulate cytoskeleton remodeling. Please access this pathway at NetSlim database.

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CompareRevisionActionTimeUserComment
75382view21:19, 21 May 2014Khanspersupdating schema
67606view11:32, 26 June 2013DdiglesOntology Term : 'prolactin signaling pathway' added !
61683view21:55, 16 April 2013MaintBotadded data source where missing
48450view16:12, 24 May 2012NetPathModified description
48449view16:09, 24 May 2012NetPathModified description
47072view00:01, 15 March 2012KhanspersModified categories
46205view22:34, 3 January 2012KhanspersUpdating gpml
46067view19:56, 12 December 2011KhanspersUpdating gpml
45275view18:58, 7 October 2011KhanspersOntology Term : 'peptide and protein hormone signaling pathway' added !
44737view08:20, 29 September 2011JyotiModified description
44637view18:26, 22 September 2011KhanspersNew pathway

External references

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NameTypeDatabase referenceComment
PTPN1Protein5770 (Entrez Gene)
PRLRProtein5618 (Entrez Gene)
RPS6Protein6194 (Entrez Gene)
PIK3R2Protein5296 (Entrez Gene)
PIK3CAProtein5290 (Entrez Gene)
JAK1Protein3716 (Entrez Gene)
SHC1Protein6464 (Entrez Gene)
PTPN6Protein5777 (Entrez Gene)
SOS1Protein6654 (Entrez Gene)
STAT5AProtein6776 (Entrez Gene)
PPIAProtein5478 (Entrez Gene)
STAT5BProtein6777 (Entrez Gene)
MAPK14Protein1432 (Entrez Gene)
CTSDProtein1509 (Entrez Gene)
FYNProtein2534 (Entrez Gene)
PRLProtein5617 (Entrez Gene)
PXNProtein5829 (Entrez Gene)
NFKBIBProtein4793 (Entrez Gene)
MAP2K1Protein5604 (Entrez Gene)
SH2B1Protein2316 (Entrez Gene)
IRF1Rna3659 (Entrez Gene)
CASP3Protein836 (Entrez Gene)
MTORProtein2475 (Entrez Gene)
CISHProtein1154 (Entrez Gene)
MAPK8Protein5599 (Entrez Gene)
PPIBGeneProduct5479 (Entrez Gene)
JAK2Protein3717 (Entrez Gene)
FOSProtein2353 (Entrez Gene)
PTPN11Protein5781 (Entrez Gene)
MYCProtein4609 (Entrez Gene)
IRS2Protein8660 (Entrez Gene)
NFKBIAProtein4792 (Entrez Gene)
PTK2Protein5747 (Entrez Gene)
RPS6KA2Protein6196 (Entrez Gene)
YWHAGProtein7532 (Entrez Gene)
MAPK3Protein5595 (Entrez Gene)
HRASProtein3265 (Entrez Gene)
RELAProtein5970 (Entrez Gene)
TECProtein7006 (Entrez Gene)
PAK1Protein5058 (Entrez Gene)
FLNAProtein2316 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
SIRPAProtein140885 (Entrez Gene)
NOS2Rna4843 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
PIAS3Protein10401 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
JUNProtein3725 (Entrez Gene)
MAPK9Protein5601 (Entrez Gene)
SOCS3Protein9021 (Entrez Gene)
GSK3BProtein2932 (Entrez Gene)
AGAP2Protein116986 (Entrez Gene)
EIF4EBP1Protein1978 (Entrez Gene)
SOCS2Protein8835 (Entrez Gene)
VAV1Protein7409 (Entrez Gene)
PIK3CGProtein5294 (Entrez Gene)
GRB2Protein2885 (Entrez Gene)
PIK3CBProtein5291 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
ApoptosisPathwayWP254 (WikiPathways)
IRS1Protein3667 (Entrez Gene)
Regulation of actin cytoskeletonPathwayWP51 (WikiPathways)
ZAP70Protein7535 (Entrez Gene)
STAT1Protein6772 (Entrez Gene)
RPS6KB1Protein6198 (Entrez Gene)
CBLProtein867 (Entrez Gene)
ELK1Protein2002 (Entrez Gene)
NEK3Protein4752 (Entrez Gene)
STAT3Protein6774 (Entrez Gene)
GAB2Protein9846 (Entrez Gene)
YWHAZProtein7534 (Entrez Gene)
ERRB2Protein2064 (Entrez Gene)
RAF1Protein5894 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAP2K2Protein5605 (Entrez Gene)
ITGB1Protein3688 (Entrez Gene)
SOCS1Protein8651 (Entrez Gene)
VAV2Protein7410 (Entrez Gene)
SRCProtein6714 (Entrez Gene)
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