TY - JOUR
T1 - α-Catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion
AU - Wood, Megan N.
AU - Ishiyama, Noboru
AU - Singaram, Indira
AU - Chung, Connie M.
AU - Flozak, Annette S.
AU - Yemelyanov, Alex
AU - Ikura, Mitsu
AU - Cho, Wonhwa
AU - Gottardi, Cara J.
N1 - Funding Information:
We thank our Northwestern University colleagues, Volodya Gelfand, Josh Rappoport, Farida Korobova, Dave Kirchenbuchler, Dina Arvanitis, Sergey Troyanovsky, and Richard A. Anderson (University of Wisconsin), for advice and discussion. This work was supported by the National Science Foundation Graduate Research Program (grant DGE-1324585) and a John N. Nicholson Fellowship to M.N. Wood, Canadian Institutes of Health Research grant 130267 to N. Ishiyama and M. Ikura, National Institutes of Health grant R35GM122530 to W. Cho, National Institutes of Health grants GM076561 and P01HL071643 to C.J. Gottardi and cores (Skin Disease Research Center [grant P30AR057216], Flow Cytometry [National Cancer Institute grants CA0605531 and S10OD011996], and Center for Advanced Microscopy [National Cancer Institute Cancer Center Support Grants P30 CA060553, S10 RR031680, and S10OD016342]). The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Wood et al.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - A unique feature of α-catenin localized outside the cadherin-catenin complex is its capacity to form homodimers, but the subcellular localization and functions of this form of α-catenin remain incompletely understood. We identified a cadherin-free form of α-catenin that is recruited to the leading edge of migrating cells in a phosphatidylinositol 3-kinase- dependent manner. Surface plasmon resonance analysis shows that α-catenin homodimers, but not monomers, selectively bind phosphatidylinositol-3,4,5-trisphosphate-containing lipid vesicles with high affinity, where three basic residues, K488, K493, and R496, contribute to binding. Chemical-induced dimerization of α-catenin containing a synthetic dimerization domain promotes its accumulation within lamellipodia and elaboration of protrusions with extended filopodia, which are attenuated in the α-cateninKKR < 3A mutant. Cells restored with a full-length, natively homodimerizing form of α-cateninKKR < 3A display reduced membrane recruitment, altered epithelial sheet migrations, and weaker cell-cell adhesion compared with WT α-catenin. These findings show that α-catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion and migration, suggesting that phosphoinositide binding may be a defining feature of α-catenin function outside the cadherin-catenin complex.
AB - A unique feature of α-catenin localized outside the cadherin-catenin complex is its capacity to form homodimers, but the subcellular localization and functions of this form of α-catenin remain incompletely understood. We identified a cadherin-free form of α-catenin that is recruited to the leading edge of migrating cells in a phosphatidylinositol 3-kinase- dependent manner. Surface plasmon resonance analysis shows that α-catenin homodimers, but not monomers, selectively bind phosphatidylinositol-3,4,5-trisphosphate-containing lipid vesicles with high affinity, where three basic residues, K488, K493, and R496, contribute to binding. Chemical-induced dimerization of α-catenin containing a synthetic dimerization domain promotes its accumulation within lamellipodia and elaboration of protrusions with extended filopodia, which are attenuated in the α-cateninKKR < 3A mutant. Cells restored with a full-length, natively homodimerizing form of α-cateninKKR < 3A display reduced membrane recruitment, altered epithelial sheet migrations, and weaker cell-cell adhesion compared with WT α-catenin. These findings show that α-catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion and migration, suggesting that phosphoinositide binding may be a defining feature of α-catenin function outside the cadherin-catenin complex.
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U2 - 10.1083/jcb.201612006
DO - 10.1083/jcb.201612006
M3 - Article
C2 - 28874417
AN - SCOPUS:85032913965
VL - 216
SP - 3767
EP - 3783
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 11
ER -