Prolactin signaling pathway (WP2037)

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 [http://www.netpath.org/netslim/NetSlim_56 NetSlim] database. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2037 CPTAC Assay Portal]
last edited

Authors

Khanspers, Jyoti, NetPath, MaintBot, Ddigles, Egonw, Mkutmon, AlexanderPico, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: prolactin signaling pathway

Participants

Label Type Compact Identifier
PIK3CA Protein ncbigene:5290
PRLR Protein ncbigene:5618
PIK3R2 Protein ncbigene:5296
Regulation of actin cytoskeleton Pathway wikipathways:WP51
PIAS3 Protein ncbigene:10401
NOS2 Rna ncbigene:4843
NFKBIA Protein ncbigene:4792
STAT5B Protein ncbigene:6777
JAK1 Protein ncbigene:3716
Apoptosis Pathway wikipathways:WP254
STAT5A Protein ncbigene:6776
SOCS2 Rna ncbigene:8835
PIK3CB Protein ncbigene:5291
CASP3 Protein ncbigene:836
STAT5A Protein ncbigene:6776
PRL Protein ncbigene:5617
NFKBIB Protein ncbigene:4793
MYC Protein ncbigene:4609
SOCS3 Rna ncbigene:9021
PRL GeneProduct ncbigene:5617
PPIB Protein ncbigene:5479
PAK1 Protein ncbigene:5058
AGAP2 Protein ncbigene:116986
PTPN6 Protein ncbigene:5777
PPIB Protein ncbigene:5479
FOS Protein ncbigene:2353
JUN Protein ncbigene:3725
PPIB GeneProduct ncbigene:5479
SH2B1 Protein ncbigene:2316
MAPK3 Protein ncbigene:5595
RPS6KA2 Protein ncbigene:6196
CTSD Protein ncbigene:1509
STAT5A Protein ncbigene:6776
PIK3CG Protein ncbigene:5294
NFKB1 Protein ncbigene:4790
RELA Protein ncbigene:5970
PRL Protein ncbigene:5617
CISH Rna ncbigene:1154
STAT1 Protein ncbigene:6772
STAT1 Protein ncbigene:6772
CBL Protein ncbigene:867
RELA Protein ncbigene:5970
NEK3 Protein ncbigene:4752
GAB2 Protein ncbigene:9846
CISH Protein ncbigene:1154
ERRB2 Protein ncbigene:2064
MAPK1 Protein ncbigene:5594
ITGB1 Protein ncbigene:3688
VAV2 Protein ncbigene:7410
FLNA Protein ncbigene:2316
IRF1 Rna ncbigene:3659
SIRPA Protein ncbigene:140885
PPIA Protein ncbigene:5478
PRLR Protein ncbigene:5618
MAPK3 Protein ncbigene:5595
RAC1 Protein ncbigene:5879
MAPK1 Protein ncbigene:5594
MTOR Protein ncbigene:2475
AKT1 Protein ncbigene:207
RPS6 Protein ncbigene:6194
MAPK9 Protein ncbigene:5601
MAPK8 Protein ncbigene:5599
GSK3B Protein ncbigene:2932
MAPK14 Protein ncbigene:1432
EIF4EBP1 Protein ncbigene:1978
PRL Protein ncbigene:5617
SOCS3 Protein ncbigene:9021
JAK2 Protein ncbigene:3717
VAV1 Protein ncbigene:7409
STAT5A Protein ncbigene:6776
STAT5B Protein ncbigene:6777
SHC1 Protein ncbigene:6464
GRB2 Protein ncbigene:2885
PTPN11 Protein ncbigene:5781
SOCS2 Protein ncbigene:8835
PIK3R1 Protein ncbigene:5295
FYN Protein ncbigene:2534
IRS1 Protein ncbigene:3667
IRS2 Protein ncbigene:8660
ZAP70 Protein ncbigene:7535
PTPN1 Protein ncbigene:5770
RPS6KB1 Protein ncbigene:6198
PTK2 Protein ncbigene:5747
ELK1 Protein ncbigene:2002
PXN Protein ncbigene:5829
STAT3 Protein ncbigene:6774
STAT5A Protein ncbigene:6776
YWHAG Protein ncbigene:7532
YWHAZ Protein ncbigene:7534
SOS1 Protein ncbigene:6654
RAF1 Protein ncbigene:5894
HRAS Protein ncbigene:3265
MAP2K2 Protein ncbigene:5605
MAP2K1 Protein ncbigene:5604
SOCS1 Protein ncbigene:8651
TEC Protein ncbigene:7006
SRC Protein ncbigene:6714

References