Growth factors induce differential phosphorylation profiles of the Hrs-STAM complex: a common node in signalling networks with signal-specific properties

• Published in: Biochemical journal Vol. 389; no. Pt 3; pp. 629 - 636
• Main Authors: Row, Paula E, Clague, Michael J, Urbé, Sylvie
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 01.08.2005
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Cell Line, Tumor; Endosomal Sorting Complexes Required for Transport; Growth Substances - physiology; Humans; Phosphoproteins - metabolism; Phosphorylation; Proto-Oncogene Proteins c-met - physiology; Receptor, Epidermal Growth Factor - physiology; Receptors, Platelet-Derived Growth Factor - physiology; Signal Transduction - physiology
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20050067

Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (signal-transducing adaptor molecule) form a heterodimeric complex that associates with endosomal membranes and is tyrosine-phosphorylated in response to a variety of growth factors including EGF (epidermal growth factor), HGF (hepatocyte growth factor) and PDGF (platelet-derived growth factor). Phosphorylation of the Hrs-STAM complex requires receptor endocytosis. We show that an intact UIM (ubiquitin interaction motif) within Hrs is a conserved requirement for Hrs phosphorylation downstream of both EGF and HGF stimulations. Consistent with this, expression of a dominant-negative form of the E3 ubiquitin ligase, c-Cbl, inhibits EGF- and HGF-dependent Hrs phosphorylation. Despite this conservation, kinase inhibitor profiles using PP1 (4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and SU6656 indicate that distinct non-receptor tyrosine kinases couple EGF, HGF and PDGF stimulation with the tyrosine phosphorylation of the Hrs-STAM complex. Crucially, analysis with phospho-specific antibodies indicates that these kinases generate a signal-specific, combinatorial phosphorylation profile of the Hrs-STAM complex, with the potential of diversifying tyrosine kinase receptor signalling through a common element.