Prolactin inhibits activity of pyruvate kinase M2 to stimulate cell proliferation.
Mitogenic and prosurvival effects underlie the tumorigenic roles of prolactin (PRL) in the pathogenesis of breast cancer. PRL signaling is mediated through its receptor (PRLr). A proteomics screen identified the pyruvate kinase M2 (PKM2), a glycolytic enzyme known to play an important role in tumorigenesis, as a protein that constitutively interacts with PRLr. Treatment of cells with PRL inhibited pyruvate kinase activity and increased the lactate content in human cells in a manner that was dependent on the abundance of PRLr, activation of Janus kinase 2, and tyrosine phosphorylation of the intracellular domain of PRLr. Knockdown of PKM2 attenuated PRL-stimulated cell proliferation. The extent of this proliferation was rescued by the knock-in of the wild-type PKM2 but not of its mutant insensitive to PRL-mediated inhibition. We discuss a hypothesis that the inhibition of PKM2 by PRL contributes to the PRL-stimulated cell proliferation.
Varghese
Bentley
B
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4539, USA.
Swaminathan
Gayathri
G
Plotnikov
Alexander
A
Tzimas
Christos
C
Yang
Ning
N
Rui
Hallgeir
H
Fuchs
Serge Y
SY
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D010766:Phosphorylation; D011388:Prolactin / Q000494:pharmacology*; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
D011981:Receptors, Prolactin; D019344:Lactic Acid; D014443:Tyrosine; D011388:Prolactin; D011770:Pyruvate Kinase; C507924:JAK2 protein, human; D053614:Janus Kinase 2