Abstract
Cbl proteins downregulate metazoan signalling pathways by ubiquitylating receptor tyrosine kinases, thereby targeting them for degradation. They contain a phosphotyrosine-binding region, comprising an EF-hand and an SH2 domain, linked to an E3 ubiquitin-ligase domain. CblA, a Dictyostelium homologue of the Cbl proteins, contains all three conserved domains. In a cblA(-) strain early development occurs normally but migrating cblA(-) slugs frequently fragment and the basal disc of the culminants that are formed are absent or much reduced. These are characteristic features of mutants in signalling by DIF-1, the low-molecular-mass prestalk and stalk cell inducer. Tyrosine phosphorylation of STATc is induced by DIF-1 but in the cblA(-) strain this response is attenuated relative to parental cells. We present evidence that CblA fulfils this function, as a positive regulator of STATc tyrosine phosphorylation, by downregulating PTP3, the protein tyrosine phosphatase responsible for dephosphorylating STATc. Thus Cbl proteins have an ancient origin but, whereas metazoan Cbl proteins regulate tyrosine kinases, the Dictyostelium Cbl regulates via a tyrosine phosphatase.
Highlights
Binding of extracellular factors to receptor tyrosine kinases (RTKs) triggers signal transduction pathways that are used in animals to regulate processes such as cell proliferation, differentiation, motility and survival
We have identified a Cbl-like protein in Dictyostelium, a facultative multicellular organism that possesses a small but diverse set of SH2 domain proteins
Understanding the regulation of PTP3 activity is key to understanding STATc activation and we present evidence that the Dictyostelium Cbl homologue, CblA, upregulates STATc tyrosine phosphorylation via an inhibitory effect on PTP3 accumulation
Summary
Binding of extracellular factors to receptor tyrosine kinases (RTKs) triggers signal transduction pathways that are used in animals to regulate processes such as cell proliferation, differentiation, motility and survival. In order to guarantee the temporal and spatial control of RTK-mediated signalling, RTK activity has to be tightly regulated One such regulatory mechanism, which serves to attenuate RTK signalling, is the removal of receptor complexes from the membrane by endocytosis and subsequent degradation. This promotes RTK endocytosis and endosomal sorting of RTKs for lysosomal degradation (de Melker et al, 2001; Dikic and Giordano, 2003; Levkowitz et al, 1998; Longva et al, 2002) In addition to their role in RTK signal termination, Cbl proteins are involved in the mediation of positive RTK signalling to downstream targets by acting as multi-domain adaptors (Swaminathan and Tsygankov, 2006)
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