Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B.
Growth hormone binds to its membrane receptor (GHR), whereby it regulates many cellular functions, including proliferation, differentiation and chemotaxis. However, although the activation of growth hormone-mediated signalling is well understood, the precise mechanism responsible for its regulation has not been elucidated. Here, we demonstrate that phospholipase Cgamma1 (PLCgamma1) modulates the action of growth hormone-mediated signalling by interacting with tyrosine kinase Jak2 (janus kinase 2) in a growth hormone-dependent manner. In the absence of PLCgamma1 (PLCgamma1(-/-)), growth hormone-induced JAK2 and STAT5 phosphorylation significantly increased in mouse embryonic fibroblasts (MEFs). Furthermore, the re-expression of PLCgamma1 reduced growth hormone-induced Jak2 activation. Growth hormone-induced Jak2 phosphorylation was enhanced by siRNA-specific knockdown of PLCgamma1. Interestingly, PLCgamma1 physically linked Jak2 and protein tyrosine phosphatase-1B (PTP-1B) by binding to both using different domains, and this process was implicated in the modulation of cytokine signalling through Jak2. In addition, in PLCgamma1(-/-) MEFs, growth hormone-dependent c-Fos activation was upregulated and growth hormone-induced proliferation was potentiated. These results suggest that PLCgamma1 has a key function in the regulation of growth hormone-mediated signalling by negatively regulating Jak2 activation.
Choi
Jang Hyun
JH
National Research Laboratory of Signaling Network, Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, 790-784, Republic of Korea.
Kim
Hyeon Soo
HS
Kim
Sun-Hee
SH
Yang
Yong Ryoul
YR
Bae
Yun Soo
YS
Chang
Jong-Soo
JS
Kwon
H Moo
HM
Ryu
Sung Ho
SH
Suh
Pann-Ghill
PG
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D051966:Phospholipase C gamma / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D013006:Growth Hormone; D053614:Janus Kinase 2; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; D051966:Phospholipase C gamma