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Signal Transductions of SH2/SH3: Ash/Grb-2 Downstream Signaling

1996; Elsevier BV; Linguagem: Inglês

10.1016/s1054-3589(08)60580-3

1557-8925

Tadaomi Takenawa, Kenji Miura, Hiroaki Miki, Kazutada Watanabe,

Enzyme Structure and Function

In addition to SH2 domains, many proteins regulated by receptor tyrosine kinases have SH3 domains that associate with the molecules downstream of tyrosine kinases in the signaling pathways. Varieties of proteins have been shown to have SH2 and SH3 domains. These proteins are divided into two groups. One type is SH2/SH3 proteins that have enzymatic activities, such as phospholipase Cγ, Src family tyrosine kinase, and Ras GAP. The other group is proteins that only consist of SH2 and SH3 domains such as Nck, c-Crk, and AsH/Grb-2. Because the SH3 domains function to mediate signals downstream of Ash, differences in the binding specificities of the two SH3 domains to various signaling molecules will regulate the signal direction. This chapter describes the isolation of splicing isoforms of Ash, the generation mechanism of the isoforms as revealed by genomic cloning of the Ash-encoding gene, and the roles of these isoforms in mitogenic signaling. To confirm that the three isoforms, including Ash-l, arise from a single gene by alternative splicing, we isolated genomic clones of the rat Ash-l encoding gene and analyzed gene organization by restriction mapping and nucleotide sequencing together with genomic Southern blot analysis. Although Ash-l associates with Sos and dynamin by virtue of its SH3 domains, the significance of the two SH3 domains is not necessarily clear. Because Ash-m does not associate with Sos effectively because of its defective SH3 domain, the signals through Ash-m may be transduced mainly to dynamin and other proteins without activating Ras. Then the signals possibly change cell functions involving dynamin without inducing mitogenesis. If this is the case, the direction of the signals may be regulated in the cytoplasm by the ratio between the amounts of Ash-m and Ash-I.