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PMID: 20696708 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Drosophila Mtm and class II PI3K coregulate a PI(3)P pool with cortical and endolysosomal functions.

The Journal of cell biology ·Vol. 190 ·No. 3 ·2010-08-09 ·Pages 407-25

Velichkova M, Juan J, Kadandale P, Jean S, Ribeiro I, Raman V, Stefan C, Kiger AA

Abstract

Reversible phosphoinositide phosphorylation provides a dynamic membrane code that balances opposing cell functions. However, in vivo regulatory relationships between specific kinases, phosphatases, and phosphoinositide subpools are not clear. We identified myotubularin (mtm), a Drosophila melanogaster MTM1/MTMR2 phosphoinositide phosphatase, as necessary and sufficient for immune cell protrusion formation and recruitment to wounds. Mtm-mediated turnover of endosomal phosphatidylinositol 3-phosphate (PI(3)P) pools generated by both class II and III phosphatidylinositol 3-kinases (Pi3K68D and Vps34, respectively) is needed to down-regulate membrane influx, promote efflux, and maintain endolysosomal homeostasis. Endocytosis, but not endolysosomal size, contributes to cortical remodeling by mtm function. We propose that Mtm-dependent regulation of an endosomal PI(3)P pool has separable consequences for endolysosomal homeostasis and cortical remodeling. Pi3K68D depletion (but not Vps34) rescues protrusion and distribution defects in mtm-deficient immune cells and restores functions in other tissues essential for viability. The broad interactions between mtm and class II Pi3K68D suggest a novel strategy for rebalancing PI(3)P-mediated cell functions in MTM-related human disease.

MeSH Terms
Animals Cerebral Cortex/metabolism Drosophila Homeostasis Lysosomes/metabolism Models, Biological Phosphatidylinositol 3-Kinases/metabolism Protein Tyrosine Phosphatases, Non-Receptor/metabolism
Chemicals
Phosphatidylinositol 3-Kinases Protein Tyrosine Phosphatases, Non-Receptor myotubularin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Velichkova Michaella
Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Juan Joe
Kadandale Pavan
Jean Steve
Ribeiro Inês
Raman Vignesh
Stefan Chris
Kiger Amy A
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200911020
Published
2010-08-09
Pages
407-25
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2922644
Subset
IM
Grants
NINDS NIH HHS · P30 NS047101 · United States
NIDDK NIH HHS · R01 DK017780 · United States
NIGMS NIH HHS · R01 GM078176 · United States
NIDDK NIH HHS · R01 DK17780 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1083/jcb.200911020 PMC Full Text View journal details
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