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Published on: July 13, 2019
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The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and
Xiaowen Sun1, Valerie L Su2, David A Calderwood2,3
1Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520 david.calderwood@yale.edu.
The Journal of Biological Chemistry
|August 9, 2019
Summary
The variable region of type I p21-activated kinases (PAKs) inhibits their cell-cell junction targeting. Releasing this inhibition allows PAKs to localize to cell boundaries, impacting cell adhesion and motility.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- p21-activated kinases (PAKs) are crucial serine/threonine kinases regulating cell adhesion, motility, and survival.
- Type II PAKs (PAK4-6) localize to cell-cell boundaries, influencing adhesion and colony escape.
- Type I PAKs (PAK1-3) do not localize to cell-cell junctions, unlike Type II PAKs.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the differential localization of PAK1 and PAK6.
- To identify the specific regions responsible for PAK targeting to cell-cell junctions.
- To understand the role of the variable region in regulating PAK localization and function.
Main Methods:
- Utilized chimeras and truncation mutants of PAK1 and PAK6 to analyze domain functions.
- Investigated the role of the variable region, CRIB domain, and N-terminal polybasic sequence in PAK localization.
- Assessed the requirement of Cdc42 binding for PAK targeting to cell-cell contacts.
Main Results:
- A weakly conserved variable region in PAK1 inhibits its targeting to cell-cell junctions.
- Replacing PAK1's variable region with PAK6's or deleting it ectopic PAK1 to cell-cell contacts.
- Cdc42 binding is necessary but not sufficient for PAK localization to cell-cell contacts.
- An N-terminal polybasic sequence is essential for PAK1 recruitment upon release of variable region inhibition.
Conclusions:
- All PAKs possess cell-cell boundary-targeting motifs, but the variable region acts as an inhibitory element for Type I PAKs.
- The poorly conserved, disordered variable region plays a critical role in regulating PAK localization.
- Cellular signals may release the inhibitory effect of the variable region, enabling Type I PAKs to target cell junctions.
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