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Vol. 13, Issue 5, 1550-1565, May 2002
Department of Cell and Developmental Biology, State University of
New York Upstate Medical University, Syracuse, New York 13210
The precise temporal-spatial regulation of the p21-activated
serine-threonine kinase PAK at the plasma membrane is required for
proper cytoskeletal reorganization and cell motility. However, the mechanism by which PAK localizes to focal adhesions has not yet
been elucidated. Indirect binding of PAK to the focal adhesion protein
paxillin via the Arf-GAP protein paxillin kinase linker (PKL) and
PIX/Cool suggested a mechanism. In this report, we demonstrate an
essential role for a paxillin-PKL interaction in the recruitment of
activated PAK to focal adhesions. Similar to PAK, expression of
activated Cdc42 and Rac1, but not RhoA, stimulated the translocation of
PKL from a generally diffuse localization to focal adhesions. Expression of the PAK regulatory domain (PAK1-329) or the
autoinhibitory domain (AID 83-149) induced PKL, PIX, and PAK
localization to focal adhesions, indicating a role for PAK scaffold
activation. We show PIX, but not NCK, binding to PAK is necessary for
efficient focal adhesion localization of PAK and PKL, consistent with a PAK-PIX-PKL linkage. Although PAK activation is required, it is not
sufficient for localization. The PKL amino terminus, containing the
PIX-binding site, but lacking paxillin-binding subdomain 2 (PBS2), was
unable to localize to focal adhesions and also abrogated PAK
localization. An identical result was obtained after PKL
PBS2 expression. Finally, neither PAK nor PKL was capable of localizing to
focal adhesions in cells overexpressing paxillinLD4, confirming a
requirement for this motif in recruitment of the PAK-PIX-PKL complex
to focal adhesions. These results suggest a GTP-Cdc42/GTP-Rac triggered
multistep activation cascade leading to the stimulation of the adaptor
function of PAK, which through interaction with PIX provokes a
functional PKL PBS2-paxillin LD4 association and consequent
recruitment to focal adhesions. This mechanism is probably critical for
the correct subcellular positioning of PAK, thereby influencing the
ability of PAK to coordinate cytoskeletal reorganization associated
with changes in cell shape and motility.
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