p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration.
Modulation of integrin alphavbeta5 regulates vascular permeability, angiogenesis, and tumor dissemination. In addition, we previously found a role for p21-activated kinase 4 (PAK4) in selective regulation of integrin alphavbeta5-mediated cell motility (Zhang, H., Li, Z., Viklund, E. K., and Strömblad, S. (2002) J. Cell Biol. 158, 1287-1297). This report focuses on the molecular mechanisms of this regulation. We here identified a unique PAK4-binding membrane-proximal integrin beta5-SERS-motif involved in controlling cell attachment and migration. We also mapped the integrin beta5-binding site within PAK4. We found that PAK4 binding to integrin beta5 was not sufficient to promote cell migration, but that PAK4 kinase activity was required for PAK4 promotion of cell motility. Importantly, PAK4 specifically phosphorylated the integrin beta5 subunit at Ser-759 and Ser-762 within the beta5-SERS-motif. Point mutation of these two serine residues abolished the PAK4-induced cell migration, indicating a functional role for these phosphorylations in migration. Our results may give important leads to the functional regulation of integrin alphavbeta5, with implications for vascular permeability, angiogenesis, and cancer dissemination.
Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden.
Zhilun
Z
Li
Hongquan
H
Zhang
Lars
L
Lundin
Minna
M
Thullberg
Yajuan
Y
Liu
Yunling
Y
Wang
Lena
L
Claesson-Welsh
Staffan
S
Strömblad
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002522:Chlorocebus aethiops; D006801:Humans; D039641:Integrin beta Chains / Q000737:chemistry*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry; D054462:p21-Activated Kinases / Q000737:chemistry*
D039641:Integrin beta Chains; C084344:integrin beta5; D012694:Serine; C116367:PAK4 protein, human; D054462:p21-Activated Kinases