TY - JOUR
T1 - β1 integrins with individually disrupted cytoplasmic NPxY motifs are embryonic lethal but partially active in the epidermis
AU - Meves, Alexander
AU - Stremmel, Christopher
AU - Böttcher, Ralph T.
AU - Fässler, Reinhard
N1 - Funding Information:
This work was funded by the Max Planck Society, the DFG (SFB 914), and the Mayo Clinic.
PY - 2013/12
Y1 - 2013/12
N2 - β1 Integrin adhesion is believed to require binding of talins and kindlins to the membrane proximal and distal NPxY motifs of the β1 cytoplasmic tail, respectively. To test this hypothesis, we substituted the membrane proximal and distal tyrosines (Y) of the β1 tail with alanine (A) residues (β1 Y783A; β1 Y795A) in the germline of mice. We report that β1 Y783A or β1 Y795A substitutions blocked talin or kindlin binding, respectively, and led to β1 null-like peri-implantation lethality. Expression of β1 Y783A or β1 Y795A in the epidermis, however, resulted in skin blister and hair follicle phenotypes that were considerably milder than those observed with β1 integrin gene deletion or a β1 double Y-to-A substitution (β1 YY783/795AA). In culture, defects in adhesion, spreading, and migration were more severe with the β1 Y783A than with the β1 Y795A substitution despite markedly reduced β1 Y795A integrin surface levels owing to diminished protein stability. We conclude that regulation of β1 integrin adhesion through talins and kindlins may differ substantially between stably adherent keratinocytes and cells of the developing embryo, and that β1 cytoplasmic NPxY motifs contribute individually and independent of each other to β1 function in keratinocytes.
AB - β1 Integrin adhesion is believed to require binding of talins and kindlins to the membrane proximal and distal NPxY motifs of the β1 cytoplasmic tail, respectively. To test this hypothesis, we substituted the membrane proximal and distal tyrosines (Y) of the β1 tail with alanine (A) residues (β1 Y783A; β1 Y795A) in the germline of mice. We report that β1 Y783A or β1 Y795A substitutions blocked talin or kindlin binding, respectively, and led to β1 null-like peri-implantation lethality. Expression of β1 Y783A or β1 Y795A in the epidermis, however, resulted in skin blister and hair follicle phenotypes that were considerably milder than those observed with β1 integrin gene deletion or a β1 double Y-to-A substitution (β1 YY783/795AA). In culture, defects in adhesion, spreading, and migration were more severe with the β1 Y783A than with the β1 Y795A substitution despite markedly reduced β1 Y795A integrin surface levels owing to diminished protein stability. We conclude that regulation of β1 integrin adhesion through talins and kindlins may differ substantially between stably adherent keratinocytes and cells of the developing embryo, and that β1 cytoplasmic NPxY motifs contribute individually and independent of each other to β1 function in keratinocytes.
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U2 - 10.1038/jid.2013.232
DO - 10.1038/jid.2013.232
M3 - Article
C2 - 23702582
AN - SCOPUS:84887826720
SN - 0022-202X
VL - 133
SP - 2722
EP - 2731
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 12
ER -