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SHARPIN is an endogenous inhibitor of ?1-integrin activation.

ABSTRACT: Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate ?1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of ?1-integrins in an RNAi screen. SHARPIN inhibited ?1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased ?1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin ?-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of ?1-integrins from inactive to active conformations.

SUBMITTER: Rantala JK

PROVIDER: S-EPMC3257806 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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SHARPIN is an endogenous inhibitor of β1-integrin activation.

Rantala Juha K JK Pouwels Jeroen J Pellinen Teijo T Veltel Stefan S Laasola Petra P Mattila Elina E Potter Christopher S CS Duffy Ted T Sundberg John P JP Kallioniemi Olli O Askari Janet A JA Humphries Martin J MJ Parsons Maddy M Salmi Marko M Ivaska Johanna J

Nature cell biology 20110925 11

Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate β1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of β1-integrins in an RNAi screen. SHARPIN inhibited β1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased β1-integrin activity, which was ful ...[more]

PMID: 21947080

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Project description:Shank-associated RH domain-interacting protein (SHARPIN) is a cytosolic protein that plays a key role in activation of nuclear factor κ-light-chain enhancer of activated B cells and regulation of inflammation. Furthermore, SHARPIN controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice. Arginyl-glycyl-aspartic acid (RGD), a cell adhesion tripeptide motif, is an integrin recognition sequence that facilitates PET imaging of integrin upregulation during tumor angiogenesis. We hypothesized that increased integrin activity due to loss of SHARPIN protein would affect the uptake of αvβ3-selective cyclic, dimeric peptide 68Ga-DOTA-E[c(RGDfK)]2, where E[c(RGDfk)]2 = glutamic acid-[cyclo(arginyl-glycyl-aspartic acid-D-phenylalanine-lysine)], both in several tissue types and in the tumor microenvironment. To test this hypothesis, we used RGD-based in vivo PET imaging to evaluate wild-type (wt) and SHARPIN-deficient mice (Sharpin cpdm , where cpdm = chronic proliferative dermatitis in mice) with and without melanoma tumor allografts. Methods: Sharpin cpdm mice with spontaneous null mutation in the Sharpin gene and their wt littermates with or without B16-F10-luc melanoma tumors were studied by in vivo imaging and ex vivo measurements with cyclic-RGD peptide 68Ga-DOTA-E[c(RGDfK)]2 After the last 68Ga-DOTA-E[c(RGDfK)]2 peptide PET/CT, tumors were cut into cryosections for autoradiography, histology, and immunohistochemistry. Results: The ex vivo uptake of 68Ga-DOTA-E[c(RGDfK)]2 in the mouse skin and tumor was significantly higher in Sharpin cpdm mice than in wt mice. B16-F10-luc tumors were detected 4 d after inoculation, without differences in volume or blood flow between the mouse strains. PET imaging with 68Ga-DOTA-E[c(RGDfK)]2 peptide at day 10 after inoculation revealed significantly higher uptake in the tumors transplanted into Sharpin cpdm mice than in wt mice. Furthermore, tumor vascularization was increased in the Sharpin cpdm mice. Conclusion: Sharpin cpdm mice demonstrated increased integrin activity and vascularization in B16-F10-luc melanoma tumors, as demonstrated by RGD-based in vivo PET imaging. These data indicate that SHARPIN, a protein previously associated with increased cancer growth and metastasis, may also have important regulatory roles in controlling the tumor microenvironment.

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SHARPIN is an endogenous inhibitor of ?1-integrin activation.

Publications

SHARPIN is an endogenous inhibitor of β1-integrin activation.

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