Identifikace signálních drah ovlivněných kinázou SEL-5/AAK1 u Caenorhabditis elegans

Šabata, Vojtěch

SEL-5/AAK1 belongs to the family of Numb-associated kinases (NAK), whose members perform diverse cellular functions predominantly related to clathrin-mediated endocytosis and endocytic recycling. In a previous study, we discovered that Caenorhabditis elegans SEL-5 mediates developmental processes ranging from cell migration to cell extension independently of its kinase catalytic activity. Here, we set out to explore the basal principles of SEL-5 kinase-independent functions in the context of signaling during C. elegans development. In particular, we focused on so-called Notched head phenotype which manifests by a large morphological malformation in the worm's head, caused by the reduced extension of muscle cells. We show that SEL-5 works in conjunction with the retromer complex and MIG-10/RIAM adaptor protein in a tissue non-autonomous manner in the epidermis to regulate muscle extension through a yet unrecognized mechanism. Furthermore, we validated novel interaction motifs in the SEL-5 C-terminal tail, that are, unlike SEL-5 catalytic activity, required for the SEL-5 function during the head morphogenesis. Utilizing a range of complementary genetic and modeling approaches we propose that SEL-5 uses its proline-rich motif to bind SH3 domains of ABI-1 and NCK-1 subunits of WAVE and WASP actin...

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