Abstract
The SRC homology 2 (SH2) domain protein-tyrosine phosphatase, Corkscrew (CSW) is required for signaling by receptor tyrosine kinases, including the Sevenless receptor tyrosine kinase (SEV), which directs Drosophila R7 photoreceptor cell development. To investigate the role of the different domains of CSW, we constructed domain-specific csw mutations and assayed their effects on CSW function. Our results indicate that CSW SH2 domain function is essential, but either CSW SH2 domain can fulfill this requirement. We also found that CSW and activated SEV are associated in vivo in a manner that does not require either CSW SH2 domain function or tyrosine phosphorylation of SEV. In contrast, the interaction between CSW and Daughter of Sevenless, a CSW substrate, is dependent on SH2 domain function. These results suggest that the role of the CSW SH2 domains during SEV signaling is to bind Daughter of Sevenless rather than activated SEV. We also found that although CSW protein-tyrosine phosphatase activity is required for full CSW function, a catalytically inactive CSW is capable of providing partial function. In addition, we found that deletion of either the CSW protein- tyrosine phosphatase insert or the entire CSW carboxyl terminus, which includes a conserved DRK/GRB2 SH2 domain binding sequence, does not abolish CSW function.
Highlights
Ogy 2 (SH2) domains or phosphotyrosine binding domains that bind to specific phosphorylated tyrosine residues of the Receptor tyrosine kinases (RTKs)
Our results indicate that SRC homology 2 (SH2) domain function is required for in vivo CSW function but that this requirement can be met by either CSW SH2 domain
We have shown that Sevenless receptor tyrosine kinase (SEV) and CSW can be co-immunoprecipitated from Drosophila cells, their association is independent of CSW SH2 domain function and SEV tyrosine phosphorylation
Summary
Ogy 2 (SH2) domains or phosphotyrosine binding domains that bind to specific phosphorylated tyrosine residues of the RTK The recruitment of such SH2- and phosphotyrosine binding domain-containing proteins regulates their function and leads to the activation of important intracellular signaling pathways. Among the key signaling proteins, the function of which is required during RTK signaling, is a class of protein-tyrosine phosphatases that includes SHP2 in mammals and Corkscrew (CSW) in Drosophila (reviewed in Ref. 4). Searches for SHP2 substrates in mammalian cells have led to the identification of a number of potential substrates At present, these include the transmembrane protein SHPS1/SIRP1␣, IRS-1, the PDGF receptor, and several tyrosine-phosphorylated proteins with sizes ranging from 80 to 120 kDa These include the transmembrane protein SHPS1/SIRP1␣, IRS-1, the PDGF receptor, and several tyrosine-phosphorylated proteins with sizes ranging from 80 to 120 kDa (reviewed in Refs. 4 and 8)
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