The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics
Author(s)Gertler, Frank; Nakatsu, Fubito; Perera, Rushika M.; Lucast, Louise; Zoncu, Roberto; Domin, Jan; Toomre, Derek; De Camilli, Pietro; ... Show more Show less
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Phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P[subscript 2]) and its phosphorylated product PI 3,4,5-triphosphate (PI(3,4,5)P[subscript 3]) are two major phosphoinositides concentrated at the plasma membrane. Their levels, which are tightly controlled by kinases, phospholipases, and phosphatases, regulate a variety of cellular functions, including clathrin-mediated endocytosis and receptor signaling. In this study, we show that the inositol 5-phosphatase SHIP2, a negative regulator of PI(3,4,5)P[subscript 3]-dependent signaling, also negatively regulates PI(4,5)P[subscript 2] levels and is concentrated at endocytic clathrin-coated pits (CCPs) via interactions with the scaffold protein intersectin. SHIP2 is recruited early at the pits and dissociates before fission. Both knockdown of SHIP2 expression and acute production of PI(3,4,5)P[subscript 3] shorten CCP lifetime by enhancing the rate of pit maturation, which is consistent with a positive role of both SHIP2 substrates, PI(4,5)P[subscript 2] and PI(3,4,5)P[subscript 3], on coat assembly. Because SHIP2 is a negative regulator of insulin signaling, our findings suggest the importance of the phosphoinositide metabolism at CCPs in the regulation of insulin signal output.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology
The Journal of Cell Biology
Rockefeller University Press
Nakatsu, F., R. M. Perera, L. Lucast, R. Zoncu, J. Domin, F. B. Gertler, D. Toomre, and P. De Camilli. “The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics.” The Journal of Cell Biology 190, no. 3 (August 9, 2010): 307-315.
Final published version