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

Lopez, Mitchell L.; Lo, Megan; Kung, Jennifer E.; Dudkiewicz, Małgorzata; Jang, Gwendolyn M.; Von Dollen, John; Johnson, Jeffrey R.; Krogan, Nevan J.; Pawłowski, Krzysztof LU and Jura, Natalia (2019) In Proceedings of the National Academy of Sciences of the United States of America 116(31). p.15495-15504
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CrkII, motility, NKF3 family, protein kinase, pseudokinase
in
Proceedings of the National Academy of Sciences of the United States of America
volume
116
issue
31
pages
10 pages
publisher
National Acad Sciences
external identifiers
  • scopus:85070786903
ISSN
1091-6490
DOI
10.1073/pnas.1906360116
language
English
LU publication?
yes
id
96cd356b-9e54-46a5-8474-a53587a74c2a
date added to LUP
2019-09-09 09:07:01
date last changed
2019-09-17 05:00:52
@article{96cd356b-9e54-46a5-8474-a53587a74c2a,
  abstract     = {<p>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.</p>},
  author       = {Lopez, Mitchell L. and Lo, Megan and Kung, Jennifer E. and Dudkiewicz, Małgorzata and Jang, Gwendolyn M. and Von Dollen, John and Johnson, Jeffrey R. and Krogan, Nevan J. and Pawłowski, Krzysztof and Jura, Natalia},
  issn         = {1091-6490},
  keyword      = {CrkII,motility,NKF3 family,protein kinase,pseudokinase},
  language     = {eng},
  month        = {07},
  number       = {31},
  pages        = {15495--15504},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization},
  url          = {http://dx.doi.org/10.1073/pnas.1906360116},
  volume       = {116},
  year         = {2019},
}