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Vol. 11, Issue 10, 3341-3352, October 2000
and¶
*Department of Immunology, The Scripps Research Institute, La
Jolla, California 92037; The process of macropinocytosis is an essential aspect of normal
cell function, contributing to both growth and motile processes of
cells. p21-activated kinases (PAKs) are targets for activated Rac and
Cdc42 guanosine 5'-triphosphatases and have been shown to regulate the
actin-myosin cytoskeleton. In fibroblasts PAK1 localizes to areas of
membrane ruffling, as well as to amiloride-sensitive pinocytic
vesicles. Expression of a PAK1 kinase autoinhibitory domain blocked
both platelet-derived growth factor- and RacQ61L-stimulated uptake of 70-kDa dextran particles, whereas an inactive version of this
domain did not, indicating that PAK kinase activity is required for
normal growth factor-induced macropinocytosis. The mechanisms by which
PAK modulate macropinocytosis were examined in NIH3T3 cell lines
expressing various PAK1 constructs under the control of a
tetracycline-responsive transactivator. Cells expressing PAK1
(H83,86L), a mutant that dramatically stimulates formation of dorsal
membrane ruffles, exhibited increased macropinocytic uptake of 70-kDa
dextran particles in the absence of additional stimulation. This effect
was not antagonized by coexpression of dominant-negative Rac1-T17N. In
the presence of platelet-derived growth factor, both PAK1 (H83,86L) and
a highly kinase active PAK1 (T423E) mutant dramatically enhanced the
uptake of 70-kDa dextran. Neither wild-type PAK1 nor vector controls
exhibited enhanced macropinocytosis, nor did PAK1 (H83,86L) affect
clathrin-dependent endocytic mechanisms. Active versions of PAK1
enhanced both growth factor-stimulated 70-kDa dextran uptake and
efflux, suggesting that PAK1 activity modulated pinocytic vesicle
cycling. These data indicate that PAK1 plays an important regulatory
role in the process of macropinocytosis, perhaps related to the
requirement for PAK in directed cell motility.
Section of Molecular Cell and
Developmental Biology, The Institute for Cellular and Molecular
Biology, University of Texas, Austin, Texas 78712; §Fox
Chase Cancer Center, Philadelphia, Pennsylvania 19111; and
Department of Cell Biology, The Scripps Research
Institute, La Jolla, California 92037
Present address: Institut für Pharmakologie
und Toxikologie, Medizinische Fakultät,
Rheinisch-Westfälische Technische Hochschule Aachen, D52057 Germany.
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