1. The podosomal-adaptor protein SH3PXD2B is essential for normal postnatal development.
- Author
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Mao M, Thedens DR, Chang B, Harris BS, Zheng QY, Johnson KR, Donahue LR, and Anderson MG
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Cell Line, Cell Surface Extensions chemistry, Cell Surface Extensions genetics, Chromosome Mapping, Craniofacial Abnormalities genetics, Craniofacial Abnormalities metabolism, Eye Abnormalities genetics, Eye Abnormalities metabolism, Female, Male, Mice genetics, Mice metabolism, Molecular Sequence Data, Mutation, Phospholipid Transfer Proteins chemistry, Phospholipid Transfer Proteins genetics, Protein Transport, Sequence Alignment, Cell Surface Extensions metabolism, Mice growth & development, Phospholipid Transfer Proteins metabolism
- Abstract
Podosome-type adhesions are actin-based membrane protrusions involved in cell-matrix adhesion and extracellular matrix degradation. Despite growing knowledge of many proteins associated with podosome-type adhesions, much remains unknown concerning the function of podosomal proteins at the level of the whole animal. In this study, the spontaneous mouse mutant nee was used to identify a component of podosome-type adhesions that is essential for normal postnatal growth and development. Mice homozygous for the nee allele exhibited runted growth, craniofacial and skeletal abnormalities, ocular anterior segment dysgenesis, and hearing impairment. Adults also exhibited infertility and a form of lipodystrophy. Using genetic mapping and DNA sequencing, the cause of nee phenotypes was identified as a 1-bp deletion within the Sh3pxd2b gene on mouse Chromosome 11. Whereas the wild-type Sh3pxd2b gene is predicted to encode a protein with one PX domain and four SH3 domains, the nee mutation is predicted to cause a frameshift and a protein truncation altering a portion of the third SH3 domain and deleting all of the fourth SH3 domain. The SH3PXD2B protein is believed to be an important component of podosomes likely to mediate protein-protein interactions with membrane-spanning metalloproteinases. Testing this directly, SH3PXD2B localized to podosomes in constitutively active Src-transfected fibroblasts and through its last SH3 domain associated with a transmembrane member of a disintegrin and metalloproteinase family of proteins, ADAM15. These results identify SH3PXD2B as a podosomal-adaptor protein required for postnatal growth and development, particularly within physiologic contexts involving extracellular matrix regulation.
- Published
- 2009
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