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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Mitchell L. Lopez
  • Megan Lo
  • Jennifer E. Kung
  • Małgorzata Dudkiewicz
  • Gwendolyn M. Jang
  • John Von Dollen
  • Jeffrey R. Johnson
  • Nevan J. Krogan
  • Krzysztof Pawłowski
  • Natalia Jura
Organisations
External organisations
  • Warsaw University of Life Sciences
  • University of California, San Francisco
  • The J. David Gladstone Institutes
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • CrkII, motility, NKF3 family, protein kinase, pseudokinase
Original languageEnglish
Pages (from-to)15495-15504
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number31
Publication statusPublished - 2019 Jul 30
Publication categoryResearch
Peer-reviewedYes