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Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15495-15504. doi: 10.1073/pnas.1906360116. Epub 2019 Jul 16.

PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization.

Author information

1
Cardiovascular Research Institute, University of California, San Francisco, CA 94158.
2
Faculty of Agriculture and Biology, Warsaw University of Life Sciences, 02-776 Warsaw, Poland.
3
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
4
Quantitative Biosciences Institute, University of California, San Francisco, CA 94158.
5
J. David Gladstone Institutes, San Francisco, CA 94158.
6
Department of Translational Medicine, Lund University, 221 00 Lund, Sweden.
7
Cardiovascular Research Institute, University of California, San Francisco, CA 94158; natalia.jura@ucsf.edu.

Abstract

Members of the New Kinase Family 3 (NKF3), PEAK1/SgK269 and Pragmin/SgK223 pseudokinases, have emerged as important regulators of cell motility and cancer progression. Here, we demonstrate that C19orf35 (PEAK3), a newly identified member of the NKF3 family, is a kinase-like protein evolutionarily conserved across mammals and birds and a regulator of cell motility. In contrast to its family members, which promote cell elongation when overexpressed in cells, PEAK3 overexpression does not have an elongating effect on cell shape but instead is associated with loss of actin filaments. Through an unbiased search for PEAK3 binding partners, we identified several regulators of cell motility, including the adaptor protein CrkII. We show that by binding to CrkII, PEAK3 prevents the formation of CrkII-dependent membrane ruffling. This function of PEAK3 is reliant upon its dimerization, which is mediated through a split helical dimerization domain conserved among all NKF3 family members. Disruption of the conserved DFG motif in the PEAK3 pseudokinase domain also interferes with its ability to dimerize and subsequently bind CrkII, suggesting that the conformation of the pseudokinase domain might play an important role in PEAK3 signaling. Hence, our data identify PEAK3 as an NKF3 family member with a unique role in cell motility driven by dimerization of its pseudokinase domain.

KEYWORDS:

CrkII; NKF3 family; motility; protein kinase; pseudokinase

PMID:
31311869
PMCID:
PMC6681764
[Available on 2020-01-16]
DOI:
10.1073/pnas.1906360116

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