Abstract
Insulin/insulin-like growth factor signaling (IIS) plays a pivotal role in the regulation of growth at the cellular and the organismal level during animal development. Flies with impaired IIS are developmentally delayed and small due to fewer and smaller cells. In the search for new growth-promoting genes, we identified mutations in the gene encoding Lnk, the single fly member of the SH2B family of adaptor molecules. Flies lacking lnk function are viable but severely reduced in size. Furthermore, lnk mutants display phenotypes reminiscent of reduced IIS, such as developmental delay, female sterility, and accumulation of lipids. Genetic epistasis analysis places lnk downstream of the insulin receptor (InR) and upstream of phosphoinositide 3-kinase (PI3K) in the IIS cascade, at the same level as chico (encoding the single fly insulin receptor substrate [IRS] homolog). Both chico and lnk mutant larvae display a similar reduction in IIS activity as judged by the localization of a PIP3 reporter and the phosphorylation of protein kinase B (PKB). Furthermore, chico; lnk double mutants are synthetically lethal, suggesting that Chico and Lnk fulfill independent but partially redundant functions in the activation of PI3K upon InR stimulation.
Highlights
The control of cell, organ and body size is tightly regulated to ensure proper development of multicellular organisms
Chico gets phosphorylated upon insulin-like growth factor signaling (IIS) pathway activation, providing binding sites for the Src Homology 2 (SH2) domain of p60, the regulatory subunit of phosphoinositide 3-kinase (PI3K)
Whereas SH2B3 (Lnk) has been described to function exclusively by negatively regulating receptor kinases that are specialized in the development of a subset of immune and hematopoietic cells, the picture for the other two family members is not as clear yet [18]. Both SH2B1 and SH2B2 have been shown to be directly involved in the regulation of JAK tyrosine kinases and of IIS, their specificities and physiological functions are complex and
Summary
The control of cell, organ and body size is tightly regulated to ensure proper development of multicellular organisms. A novel family of adaptor proteins, the SH2B family, has been identified in mammals It consists of three members – SH2B1 (SH2B/PSM), SH2B2 (APS) and SH2B3 (Lnk) – that share a common protein structure with an N-terminal proline-rich stretch, a PH domain, an SH2 domain and a highly conserved Cterminal Cbl recognition motif [10,11,12]. They have been shown to regulate signal transduction by receptor tyrosine kinases such as the InR, IGF-I receptor and receptors for nerve growth factor, hepatocyte growth factor, platelet-derived growth factor and fibroblast growth factor, as well as by the JAK family of tyrosine kinases [11,13,14,15,16,17]. Both SH2B1 and SH2B2 have been shown to be directly involved in the regulation of JAK tyrosine kinases and of IIS, their specificities and physiological functions are complex and
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