title: Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B.
abstract: 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.
authors.affiliation: National Research Laboratory of Signaling Network, Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, 790-784, Republic of Korea.
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Yong Ryoul
authors.initials: YR
authors.lastname: Yang
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Chang
authors.forename: H Moo
authors.initials: HM
authors.lastname: Kwon
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
mesh_terms: 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
chemical_list: 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