Inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2

Tomas Rojas; Weiwei Cheng; Zhe Gao; Xiaoqi Liu; Yakun Wang; Adarsha P Malla; Alfred C Chin; Lewis H Romer; Solomon H Snyder; Chenglai Fu

doi:10.1073/pnas.1817001116

Inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2

Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3278-3287. doi: 10.1073/pnas.1817001116. Epub 2019 Feb 4.

Authors

Tomas Rojas¹, Weiwei Cheng², Zhe Gao³, Xiaoqi Liu³, Yakun Wang³, Adarsha P Malla¹, Alfred C Chin¹, Lewis H Romer^{4

5

6

7

8}, Solomon H Snyder^{9

10

11}, Chenglai Fu¹²

Affiliations

¹ Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
² Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
³ Department of Physiology and Pathophysiology, Tianjin Medical University, 300070 Tianjin, China.
⁴ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287.
⁵ Department of Cell Biology, Johns Hopkins University, Baltimore, MD, 21287.
⁶ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21287.
⁷ Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21287.
⁸ Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD 21287.
⁹ Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; ssnyder@jhmi.edu chenglaifu@tmu.edu.cn.
¹⁰ Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹¹ Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
¹² Department of Physiology and Pathophysiology, Tianjin Medical University, 300070 Tianjin, China; ssnyder@jhmi.edu chenglaifu@tmu.edu.cn.

Abstract

Cells express a family of three inositol hexakisphosphate kinases (IP6Ks). Although sharing the same enzymatic activity, individual IP6Ks mediate different cellular processes. Here we report that IP6K3 is enriched at the leading edge of migrating cells where it associates with dynein intermediate chain 2 (DIC2). Using immunofluorescence microscopy and total internal reflection fluorescence microscopy, we found that DIC2 and IP6K3 are recruited interdependently to the leading edge of migrating cells, where they function coordinately to enhance the turnover of focal adhesions. Deletion of IP6K3 causes defects in cell motility and neuronal dendritic growth, eventually leading to brain malformations. Our results reveal a mechanism whereby IP6K3 functions in coordination with DIC2 in a confined intracellular microenvironment to promote focal adhesion turnover.

Keywords: FAK; IP6K; cell migration; dynein; focal adhesion.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Brain / metabolism
Brain / pathology
Cell Adhesion / genetics
Cell Movement / genetics
Cellular Microenvironment / genetics
Cytoplasmic Dyneins / genetics*
Dendrites / genetics*
Focal Adhesions / genetics
HEK293 Cells
Humans
Neurons / metabolism
Phosphotransferases (Phosphate Group Acceptor) / genetics*

Substances

Phosphotransferases (Phosphate Group Acceptor)
inositol hexakisphosphate kinase
Cytoplasmic Dyneins

Abstract

Publication types

MeSH terms

Substances

Grants and funding