IPMK-1 (inositol phosphate multikinase) is required for integrin adhesion complex organization and muscle cell adhesion in C. elegans

Abstract Integrin adhesion complexes (IACs) are a network of proteins that anchor cells to the extracellular matrix. In C. elegans muscle IACs exist at the bases of dense bodies and M-lines, and at the boundaries of adjacent muscle cells (MCBs). Proper assembly of IACs requires the RacGEF PIX-1 and members of the PIX-1 pathway. We report that investigation into the original Million Mutation Project strain that led us to uncover the role of PIX-1 in muscle, revealed a genetic enhancer of the pix-1 phenotype. Genetic mapping shows that the enhancer is a recessive mutation in ipmk-1. ipmk-1 encodes inositol phosphate multikinase and converts PIP2 to PIP3, IP3 to IP4, and IP4 to IP5. pix-1 loss of function mutants show reduced accumulation of IAC proteins at the MCB, and ipmk-1; pix-1 doubles additionally display large gaps between muscle cells. ipmk-1 similarly enhances other members of the PIX pathway including PAK-1, and the RacGAP RRC-1. Lack of ipmk-1 itself shows abnormal clumping of IAC proteins at MCBs and decreased animal locomotion. Muscle activity contributes to formation of the gap, since suppression occurs by paralysis induced by unc-13. The MCB defect of ipmk-1 is not due to decreased IP3 and Ca2+ signaling from analysis of ipmk-1; ipp-5 doubles and GCaMP Ca2+ measurements. PIP3 localizes to the MCB and between dense bodies and is decreased in ipmk-1. Mutants in DAF-18 (PTEN), which converts PIP3 to PIP2, partially suppress the clumping phenotype of ipmk-1, suggesting that the PIP3 to PIP2 ratio is important for IAC organization.