Modulation of integrin activity is vital for morphogenesis.
Cells can vary their adhesive properties by modulating the affinity of integrin receptors. The activation and inactivation of integrins by inside-out mechanisms acting on the cytoplasmic domains of the integrin subunits has been demonstrated in platelets, lymphocytes, and keratinocytes. We show that in the embryo, normal morphogenesis requires the alpha subunit cytoplasmic domain to control integrin adhesion at the right times and places. PS2 integrin (alphaPS2betaPS) adhesion is normally restricted to the muscle termini, where it is required for attaching the muscles to the ends of other muscles and to specialized epidermal cells. Replacing the wild-type alphaPS2 with mutant forms containing cytoplasmic domain deletions results in the rescue of the majority of defects associated with the absence of the alphaPS2 subunit, however, the mutant PS2 integrins are excessively active. Muscles containing these mutant integrins make extra muscle attachments at aberrant positions on the muscle surface, disrupting the muscle pattern and causing embryonic lethality. A gain- of-function phenotype is not observed in the visceral mesoderm, showing that regulation of integrin activity is tissue-specific. These results suggest that the alphaPS2 subunit cytoplasmic domain is required for inside-out regulation of integrin affinity, as has been seen with the integrin alphaIIbbeta3.
Martin-Bermudo
M D
MD
Wellcome/CRC Institute, Cambridge CB2 1QR, England; and Department of Biochemistry, Cambridge University, Cambridge CB2 1QW, England.
Dunin-Borkowski
O M
OM
Brown
N H
NH
D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D003593:Cytoplasm / Q000502:physiology; D017931:DNA Primers; D004330:Drosophila / Q000196:embryology* / Q000235:genetics; D029721:Drosophila Proteins; D004625:Embryo, Nonmammalian / Q000502:physiology*; D005091:Exons; D005804:Genes, Lethal; D039001:Integrin alpha Chains; D016023:Integrins / Q000096:biosynthesis* / Q000737:chemistry / Q000502:physiology*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009024:Morphogenesis; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D016415:Sequence Alignment
D017931:DNA Primers; D029721:Drosophila Proteins; D039001:Integrin alpha Chains; D016023:Integrins; D046911:Macromolecular Substances; C082188:if protein, Drosophila