title: Cbl competitively inhibits epidermal growth factor-induced activation of phospholipase C-gamma1.
abstract: Phospholipase C-gamma1 (PLC-gamma1) plays pivotal roles in cellular growth and proliferation through its two Src homology (SH) 2 domains and its single SH3 domain, which interact with signaling molecules in response to various growth factors and hormones. However, the role of the SH domains in the growth factor-induced regulation of PLC-gamma1 is unclear. By peptide-mass fingerprinting analysis we have identified Cbl as a binding protein for the SH3 domain of PLC-gamma1 from rat pheochromatocyte PC12 cells. Association of Cbl with PLC-gamma1 was induced by epidermal growth factor (EGF) but not by nerve growth factor (NGF). Upon EGF stimulation, both Cbl and PLC-gamma1 were recruited to the activated EGF receptor through their SH2 domains. Mutation of the SH2 domains of either Cbl or PLC-gamma1 abrogated the EGF-induced interaction of PLC-gamma1 with Cbl, indicating that SH2-mediated translocation is essential for the association of PLC-gamma1 and Cbl. Overexpression of Cbl attenuated EGF-induced tyrosine phosphorylation and the subsequent activation of PLC-gamma1 by interfering competitively with the interaction between PLC-gamma1 and EGFR. Taken together, these results provide the first indications that Cbl may be a negative regulator of intracellular signaling following EGF-induced PLC-gamma1 activation.
authors.affiliation: Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.forename: Jong Bae
authors.initials: JB
authors.lastname: Park
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Ha
authors.forename: Hebok
authors.initials: H
authors.lastname: Song
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
mesh_terms: D000818:Animals; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D066298:In Vitro Techniques; D050722:Oncogene Protein v-cbl; D016716:PC12 Cells; D051966:Phospholipase C gamma; D010766:Phosphorylation; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology
chemical_list: D050722:Oncogene Protein v-cbl; D015682:Retroviridae Proteins, Oncogenic; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010738:Type C Phospholipases; D051966:Phospholipase C gamma