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

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.

Lo, MeganUniversity of California, San Francisco (author)
Kung, Jennifer E.University of California, San Francisco (author)
Dudkiewicz, MałgorzataWarsaw University of Life Sciences (author)
Jang, Gwendolyn M.University of California, San Francisco,The J. David Gladstone Institutes (author)
Von Dollen, JohnUniversity of California, San Francisco,The J. David Gladstone Institutes (author)
Johnson, Jeffrey R.The J. David Gladstone Institutes,University of California, San Francisco (author)
Krogan, Nevan J.University of California, San Francisco,The J. David Gladstone Institutes (author)
Pawłowski, KrzysztofLund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups,Warsaw University of Life Sciences(Swepub:lu)med-kzp (author)
Jura, NataliaUniversity of California, San Francisco (author)
University of California, San FranciscoWarsaw University of Life Sciences (creator_code:org_t)

In:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences116:31, s. 15495-155041091-6490
In:Proceedings of the National Academy of Sciences: Proceedings of the National Academy of Sciences116:31, s. 15495-155040027-8424

By the author/editor: Lopez, Mitchell ...; Lo, Megan; Kung, Jennifer E ...; Dudkiewicz, Małg ...; Jang, Gwendolyn ...; Von Dollen, John; show more...; Johnson, Jeffrey ...; Krogan, Nevan J.; Pawłowski, Krzys ...; Jura, Natalia; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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