PIKE-A is required for prolactin-mediated STAT5a activation in mammary gland development.
PI 3-kinase enhancer A (PIKE-A) is critical for the activation of Akt signalling, and has an essential function in promoting cancer cell survival. However, its physiological functions are poorly understood. Here, we show that PIKE-A directly associates with both signal transducer and activator of transcription 5a (STAT5a) and prolactin (PRL) receptor, which is essential for PRL-provoked STAT5a activation and the subsequent gene transcription. Depletion of PIKE-A in HC11 epithelial cells diminished PRL-induced STAT5 activation and cyclin D1 expression, resulting in profoundly impaired cell proliferation in vitro. To confirm the function of PIKE-A in PRL signalling in vivo, we generated PIKE knockout (PIKE-/-) mice. PIKE-/- mice displayed a severe lactation defect that was characterized by enhanced apoptosis and impaired proliferation of mammary epithelial cells. At parturition, STAT5 activation and cyclin D1 expression were substantially reduced in the mammary epithelium of PIKE-/- mice. The defective mammary gland development in PIKE-/- mice was rescued by overexpression of a mammary-specific cyclin D1 transgene. These data establish a critical function for PIKE-A in mediating PRL functions.
Chan
Chi-Bun
CB
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Liu
Xia
X
Ensslin
Michael A
MA
Dillehay
Dirck L
DL
Ormandy
Christopher J
CJ
Sohn
Philip
P
Serra
Rosa
R
Ye
Keqiang
K
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005838:Genotype; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007774:Lactation / Q000235:genetics / Q000502:physiology; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011388:Prolactin / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011981:Receptors, Prolactin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*
C530105:Ccnd1 protein, mouse; D009419:Nerve Tissue Proteins; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D019938:Cyclin D1; D011388:Prolactin; D020558:GTP Phosphohydrolases; C529781:PIKE protein, mouse