CYR61 Stimulates Human Skin Fibroblast Migration through Integrin αvβ5 and Enhances Mitogenesis through Integrin αvβ3, Independent of Its Carboxyl-terminal Domain

Abstract

CYR61, an angiogenic factor and a member of the CCN protein family, is an extracellular matrix-associated, heparin-binding protein that mediates cell adhesion, promotes cell migration, and enhances growth factor-stimulated cell proliferation. CYR61 induces angiogenesis and promotes tumor growth in vivo and is expressed in dermal fibroblasts during cutaneous wound healing. It has been demonstrated recently that adhesion of primary skin fibroblasts to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans, resulting in adhesive signaling and up-regulation of matrix metalloproteinases 1 and 3. CYR61 is composed of four discrete structural domains that to the growth factor 1 and a that in growth that a CYR61 that has the is to adhesion of primary skin fibroblasts is to and growth to to CYR61 is mediated through integrin α6β1 that CYR61 to integrin in CYR61 of growth is mediated through integrin a CYR61 that mediates cell adhesion and in CYR61 promotes primary adhesion, migration, and through and CYR61 a integrin and that CYR61 to in a cell CYR61, an angiogenic factor and a member of the CCN protein family, is an extracellular matrix-associated, heparin-binding protein that mediates cell adhesion, promotes cell migration, and enhances growth factor-stimulated cell proliferation. CYR61 induces angiogenesis and promotes tumor growth in vivo and is expressed in dermal fibroblasts during cutaneous wound healing. It has been demonstrated recently that adhesion of primary skin fibroblasts to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans, resulting in adhesive signaling and up-regulation of matrix metalloproteinases 1 and 3. CYR61 is composed of four discrete structural domains that to the growth factor 1 and a that in growth that a CYR61 that has the is to adhesion of primary skin fibroblasts is to and growth to to CYR61 is mediated through integrin α6β1 that CYR61 to integrin in CYR61 of growth is mediated through integrin a CYR61 that mediates cell adhesion and in CYR61 promotes primary adhesion, migration, and through and CYR61 a integrin and that CYR61 to in a cell extracellular matrix growth factor growth factor CYR61, an angiogenic is a protein and a member of the CCN family, of and of the CCN protein is four domains that growth factor 1 and growth factor CCN four domains the of the is a the CCN through and the of CCN the of of CYR61 cell and fibroblasts and CYR61 mediates cell adhesion, cell migration, and growth of CYR61 and promotes CYR61 induces angiogenesis in vivo and enhances the of tumor in tumor and CYR61 of matrix metalloproteinases 1 and that matrix in angiogenesis and wound healing. demonstrated of CYR61 in and angiogenic cell during and in and in during cutaneous wound of the of CYR61 in cell cell surface that and of cell adhesion, migration, and CYR61 protein is a and and and CYR61 mediates cell adhesion and adhesion CYR61 the adhesion of primary fibroblasts through integrin α6β1 and cell surface heparan sulfate resulting in adhesive signaling of and of integrin and of adhesion and protein and up-regulation of matrix metalloproteinases 1 and of CYR61 and CCN four discrete structural domains that to of that domains and in domains of CCN the that of the It has been that is that a to the the of CCN a of CYR61 that the and the of a to the cell surface that the and of CYR61 in primary the that of the the of CYR61 to cell adhesion in primary fibroblasts has of cell of adhesion to CYR61 is mediated through integrin α6β1 and heparan sulfate proteoglycans, and of mediated through and that CYR61 to integrin in CYR61 a integrin a the of the and that integrin of CYR61 is skin the structural the of CYR61, CYR61 that has the in the heparin-binding the the heparin-binding that the protein to has been the of of the CYR61 protein and to to the CYR61 protein CYR61 and in the and the to the to and protein of and an 1 of protein and an the of to the adhesion of primary skin and to CYR61 adhesion in a adhesion the to cell adhesion, a adhesion to the of to the CYR61 to that the is is the that the heparin-binding in the is to adhesion to CYR61 and that CYR61 promotes of fibroblasts and and that cell to CYR61 is mediated through integrin a the in fibroblasts to CYR61 in a fibroblasts to and and the of the of CYR61, fibroblasts a adhesion to CYR61 to of heparin-binding CYR61 the the heparin-binding migration, that to the protein the of CYR61 and heparin-binding is to fibroblasts and in and to and in the that to the in the to to to of and of to CYR61 protein is mediated integrin heparan sulfate fibroblasts in a 1 to and to growth factor CYR61 1 to and to CYR61 of and of adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate integrin α6β1 a integrin integrin 1 to cell cell to CYR61 to CYR61 and cell to integrin and the integrin that adhesion, to CYR61 is mediated through integrin the migration, the CYR61 has been demonstrated to a of integrin a the integrin to and the of an cell to to a the integrin cell to CYR61 to in to in is mediated through integrin integrin is expressed in fibroblasts and has been to cell to fibroblasts a integrin to CYR61 and protein to that to CYR61 is mediated through integrin to CYR61 and in a 1 to CYR61 of and of to that CYR61 is a and and is mediated through integrin to CYR61 to a integrin CYR61 to that CYR61 to integrin in a and CYR61 and the to integrin of CYR61 and CYR61 1 to CYR61 and of and of the of the CYR61 and integrin of integrin in of CYR61 to and the of the of integrin integrin protein the and is the of the CYR61 to integrin integrin CYR61 the a that CYR61 to integrin in that CYR61 through integrin and in through CYR61 is to growth has been fibroblasts and in proliferation. a factor to fibroblasts a CYR61 in the of a of a in to CYR61 the of is and that the is CYR61 to growth enhances in of fibroblasts to CYR61 and the of and of and of integrin been to of the of CYR61, that in 1 the of CYR61 and the the the CYR61 of that an integrin the of a CYR61 of the that CYR61 is a of integrin to that integrin the of in the of integrin a integrin that integrin a in CYR61 of a the integrin the that integrin integrin mediates the of is to the protein in that the is CYR61 to growth that a integrin the domains of CYR61 and of in and 1 the CYR61 and in and fibroblasts a of and of that the and of of the angiogenic the of CYR61 is and fibroblasts is to CYR61 induces through integrin and enhances growth through integrin that CYR61 is a integrin that CYR61 integrin to and to the of the structural domains in of the CCN protein the of a that the of to a of the in a member of the CCN protein family, the is to of the in the domains to that a CCN protein the domains is of a of the protein a of to the is and cell adhesion that CCN in vivo the the CYR61 is adhesion is that is of adhesion is that is to CYR61 in to and to growth that the is the of has been to the that in the the has been to CYR61 is enhances the growth has been that CYR61 to growth is that the of and the of CYR61 and and through that CYR61 growth through integrin to that the cell and of CYR61 the and is the of integrin to cell and signaling mediated through integrin has been to of and signaling growth the that CYR61 enhances growth the is in of through integrin CYR61 has been to a of and in that CYR61 is a integrin mediates the of CYR61 in fibroblasts of protein that an and CYR61 CCN a and the in CYR61 is to and the an is growth and growth protein CYR61 is in fibroblasts of during wound and in of of and the of a of growth and that during wound that the of CYR61 to integrin is the up-regulation of and in during cutaneous wound CYR61 the of growth an angiogenic factor and a and factor CYR61 the of matrix metalloproteinases 1 and to a in angiogenesis and matrix during wound angiogenesis and wound in a is that extracellular CYR61 of of that CYR61 and CCN to is to is of and CYR61 a of heparin-binding of CYR61 to in and of is that CYR61 integrin that adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans, adhesion to to in the of mediated through and integrin integrin a integrin in a cell been to cell adhesion and through integrin and through adhesion to is mediated through integrin through integrin CYR61 is in to and a in dermal of integrin CYR61 the to the cell adhesion CYR61 the and CYR61 a CYR61 cell adhesion to the CYR61, the a factor through integrin integrin CYR61 to cell in to cell adhesion and to CYR61 in mediated through integrin and adhesion of is mediated through integrin and cell of integrin to CYR61 an CCN of CYR61 and CCN the of integrin signaling in cell and CYR61, an angiogenic is a protein and a member of the CCN family, of and of the CCN protein is four domains that growth factor 1 and growth factor CCN four domains the of the is a the CCN through and the of CCN the of of CYR61 cell and fibroblasts and CYR61 mediates cell adhesion, cell migration, and growth of CYR61 and promotes CYR61 induces angiogenesis in vivo and enhances the of tumor in tumor and CYR61 of matrix metalloproteinases 1 and that matrix in angiogenesis and wound healing. demonstrated of CYR61 in and angiogenic cell during and in and in during cutaneous wound of the of CYR61 in cell cell surface that and of cell adhesion, migration, and CYR61 protein is a and and and CYR61 mediates cell adhesion and adhesion CYR61 the adhesion of primary fibroblasts through integrin α6β1 and cell surface heparan sulfate resulting in adhesive signaling of and of integrin and of adhesion and protein and up-regulation of matrix metalloproteinases 1 and of CYR61 and CCN four discrete structural domains that to of that domains and in domains of CCN the that of the It has been that is that a to the the of CCN a of CYR61 that the and the of a to the cell surface that the and of CYR61 in primary the that of the the of CYR61 to cell adhesion in primary fibroblasts has of cell of adhesion to CYR61 is mediated through integrin α6β1 and heparan sulfate proteoglycans, and of mediated through and that CYR61 to integrin in CYR61 a integrin a the of the and that integrin of CYR61 is skin the structural the of CYR61, CYR61 that has the in the heparin-binding the the heparin-binding that the protein to has been the of of the CYR61 protein and to to the CYR61 protein CYR61 and in the and the to the to and the of to the adhesion of primary skin and to CYR61 adhesion in a adhesion the to cell adhesion, a adhesion to the of to the CYR61 to that the is is the that the heparin-binding in the is to adhesion to CYR61 and that CYR61 promotes of fibroblasts and and that cell to CYR61 is mediated through integrin a the in fibroblasts to CYR61 in a fibroblasts to and and the of the of CYR61, fibroblasts a adhesion to CYR61 to of heparin-binding CYR61 the the heparin-binding migration, that to the protein the of CYR61 and heparin-binding is to fibroblasts and in and to and in the that to the in the to to to of and of to CYR61 protein is mediated integrin heparan sulfate fibroblasts in a 1 to and to growth factor CYR61 1 to and to CYR61 of and of adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate integrin α6β1 a integrin integrin 1 to cell cell to CYR61 to CYR61 and cell to integrin and the integrin that adhesion, to CYR61 is mediated through integrin the migration, the CYR61 has been demonstrated to a of integrin a the integrin to and the of an cell to to a the integrin cell to CYR61 to in to in is mediated through integrin integrin is expressed in fibroblasts and has been to cell to fibroblasts a integrin to CYR61 and protein to that to CYR61 is mediated through integrin to CYR61 and in a 1 to CYR61 of and of to that CYR61 is a and and is mediated through integrin to CYR61 to a integrin CYR61 to that CYR61 to integrin in a and CYR61 and the to integrin of CYR61 and CYR61 1 to CYR61 and of and of the of the CYR61 and integrin of integrin in of CYR61 to and the of the of integrin integrin protein the and is the of the CYR61 to integrin integrin CYR61 the a that CYR61 to integrin in that CYR61 through integrin and in through CYR61 is to growth has been fibroblasts and in proliferation. a factor to fibroblasts a CYR61 in the of a of a in to CYR61 the of is and that the is CYR61 to growth enhances in of fibroblasts to CYR61 and the of and of and of integrin been to of the of CYR61, that in 1 the of CYR61 and the the the CYR61 of that an integrin the of a CYR61 of the that CYR61 is a of integrin to that integrin the of in the of integrin a integrin that integrin a in CYR61 of a the integrin the that integrin integrin mediates the of is to the protein in that the is CYR61 to growth that a integrin the domains of CYR61 and of in and 1 the CYR61 and in and fibroblasts a of and of CYR61 is skin the structural the of CYR61, CYR61 that has the in the heparin-binding the the heparin-binding that the protein to has been the of of the CYR61 protein and to to the CYR61 protein CYR61 and in the and the to the to and the of to the adhesion of primary skin and to CYR61 adhesion in a adhesion the to cell adhesion, a adhesion to the of to the CYR61 to that the is is the that the heparin-binding in the is to adhesion to CYR61 and that CYR61 promotes of fibroblasts and and that cell to CYR61 is mediated through integrin a the in fibroblasts to CYR61 in a fibroblasts to and and the of the of CYR61, fibroblasts a adhesion to CYR61 to of heparin-binding CYR61 the the heparin-binding migration, that to the protein the of CYR61 and heparin-binding to CYR61 protein is mediated integrin heparan sulfate fibroblasts in a 1 to and to growth factor CYR61 1 to and to CYR61 of and of adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate integrin α6β1 a integrin integrin 1 to cell cell to CYR61 to CYR61 and cell to integrin and the integrin that adhesion, to CYR61 is mediated through integrin the migration, the CYR61 has been demonstrated to a of integrin a the integrin to and the of an cell to to a the integrin cell to CYR61 to in to in is mediated through integrin integrin is expressed in fibroblasts and has been to cell to fibroblasts a integrin to CYR61 and protein to that to CYR61 is mediated through integrin to CYR61 and in a 1 to CYR61 of and of to that CYR61 is a and and is mediated through integrin to CYR61 to a integrin CYR61 to that CYR61 to integrin in a and CYR61 and the to integrin of CYR61 and CYR61 1 to CYR61 and of and of the of the CYR61 and integrin of integrin in of CYR61 to and the of the of integrin integrin protein the and is the of the CYR61 to integrin integrin CYR61 the a that CYR61 to integrin in that CYR61 through integrin and in through CYR61 is to growth has been fibroblasts and in proliferation. a factor to fibroblasts a CYR61 in the of a of a in to CYR61 the of is and that the is CYR61 to growth enhances in of fibroblasts to CYR61 and the of and of and of integrin been to of the of CYR61, that in 1 the of CYR61 and the the the CYR61 of that an integrin the of a CYR61 of the that CYR61 is a of integrin to that integrin the of in the of integrin a integrin that integrin a in CYR61 of a the integrin the that integrin integrin mediates the of is to the protein in that the is CYR61 to growth that a integrin the domains of CYR61 and of in and 1 the CYR61 and in and fibroblasts a of and of to CYR61 and that CYR61 promotes of fibroblasts and and that cell to CYR61 is mediated through integrin a the in fibroblasts to CYR61 in a fibroblasts to and and the of the of CYR61, fibroblasts a adhesion to CYR61 to of heparin-binding CYR61 the the heparin-binding migration, that to the protein the of CYR61 and heparin-binding adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate integrin α6β1 a integrin integrin 1 to cell cell to CYR61 to CYR61 and cell to integrin and the integrin that adhesion, to CYR61 is mediated through integrin the migration, the CYR61 has been demonstrated to a of integrin a the integrin to and the of an cell to to a the integrin cell to CYR61 to in to in is mediated through integrin integrin is expressed in fibroblasts and has been to cell to fibroblasts a integrin to CYR61 and protein to that to CYR61 is mediated through integrin to CYR61 and in a 1 to CYR61 of and of to that CYR61 is a and and is mediated through integrin to CYR61 to a integrin CYR61 to that CYR61 to integrin in a and CYR61 and the to integrin of CYR61 and CYR61 1 to CYR61 and of and of the of the CYR61 and integrin of integrin in of CYR61 to and the of the of integrin integrin protein the and is the of the CYR61 to integrin integrin CYR61 the a that CYR61 to integrin in that CYR61 through integrin and in through CYR61 is to growth has been fibroblasts and in proliferation. a factor to fibroblasts a CYR61 in the of a of a in to CYR61 the of is and that the is CYR61 to growth enhances in of fibroblasts to CYR61 and the of and of and of integrin been to of the of CYR61, that in 1 the of CYR61 and the the the CYR61 of that an integrin the of a CYR61 of the that CYR61 is a of integrin to that integrin the of in the of integrin a integrin that integrin a in CYR61 of a the integrin the that integrin integrin mediates the of is to the protein in that the is CYR61 to growth that a integrin the domains of CYR61 and of in and 1 the CYR61 and in and fibroblasts a of and of to CYR61 and that CYR61 promotes of fibroblasts and and that cell to CYR61 is mediated through integrin a the in fibroblasts to CYR61 in a fibroblasts to and and the of the of CYR61, fibroblasts a adhesion to CYR61 to of heparin-binding CYR61 the the heparin-binding migration, that to the protein the of CYR61 and heparin-binding adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate integrin α6β1 a integrin integrin 1 to cell cell to CYR61 to CYR61 and cell to integrin and the integrin that adhesion, to CYR61 is mediated through integrin the migration, the CYR61 has been demonstrated to a of integrin a the integrin to and the of an cell to to a the integrin cell to CYR61 to in to in is mediated through integrin integrin is expressed in fibroblasts and has been to cell to fibroblasts a integrin to CYR61 and protein to that to CYR61 is mediated through integrin that CYR61 promotes of fibroblasts and and that cell to CYR61 is mediated through integrin a the in fibroblasts to CYR61 in a fibroblasts to and and the of the of CYR61, fibroblasts a adhesion to CYR61 to of heparin-binding CYR61 the the heparin-binding migration, that to the protein the of CYR61 and heparin-binding adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate integrin α6β1 a integrin integrin 1 to cell cell to CYR61 to CYR61 and cell to integrin and the integrin that adhesion, to CYR61 is mediated through integrin the migration, the CYR61 has been demonstrated to a of integrin a the integrin to and the of an cell to to a the integrin cell to CYR61 to in to in is mediated through integrin integrin is expressed in fibroblasts and has been to cell to fibroblasts a integrin to CYR61 and protein to that to CYR61 is mediated through integrin CYR61 to that CYR61 is a and and is mediated through integrin to CYR61 to a integrin CYR61 to that CYR61 to integrin in a and CYR61 and the the of the CYR61 and integrin of integrin in of CYR61 to and the of the of integrin integrin protein the and is the of the CYR61 to integrin integrin CYR61 the a that CYR61 to integrin in that CYR61 through integrin that CYR61 is a and and is mediated through integrin to CYR61 to a integrin CYR61 to that CYR61 to integrin in a and CYR61 and the the of the CYR61 and integrin of integrin in of CYR61 to and the of the of integrin integrin protein the and is the of the CYR61 to integrin integrin CYR61 the a that CYR61 to integrin in that CYR61 through integrin CYR61 and in through CYR61 is to growth has been fibroblasts and in proliferation. a factor to fibroblasts a CYR61 in the of a of a in to CYR61 the of is and that the is CYR61 to growth integrin been to of the of CYR61, that in 1 the of CYR61 and the the the CYR61 of that an integrin the of a CYR61 of the that CYR61 is a of integrin to that integrin the of in the of integrin a integrin that integrin a in CYR61 of a the integrin the that integrin integrin mediates the of is to the protein in that the is CYR61 to growth that a integrin the domains of CYR61 and of in and 1 the CYR61 and in and fibroblasts a of and of CYR61 is to growth has been fibroblasts and in proliferation. a factor to fibroblasts a CYR61 in the of a of a in to CYR61 the of is and that the is CYR61 to growth integrin been to of the of CYR61, that in 1 the of CYR61 and the the the CYR61 of that an integrin the of a CYR61 of the that CYR61 is a of integrin to that integrin the of in the of integrin a integrin that integrin a in CYR61 of a the integrin the that integrin integrin mediates the of is to the protein in that the is CYR61 to growth that a integrin the domains of that the and of of the angiogenic the of CYR61 is and fibroblasts is to CYR61 induces through integrin and enhances growth through integrin that CYR61 is a integrin that CYR61 integrin to and to the of the structural domains in of the CCN protein the of a that the of to a of the in a member of the CCN protein family, the is to of the in the domains to that a CCN protein the domains is of a of the protein a of to the is and cell adhesion that CCN in vivo the the CYR61 is adhesion is that is of adhesion is that is to CYR61 in to and to growth that the is the of has been to the that in the the has been to CYR61 is enhances the growth has been that CYR61 to growth is that the of and the of CYR61 and and through that CYR61 growth through integrin to that the cell and of CYR61 the and is the of integrin to cell and signaling mediated through integrin has been to of and signaling growth the that CYR61 enhances growth the is in of through integrin CYR61 has been to a of and in that CYR61 is a integrin mediates the of CYR61 in fibroblasts of protein that an and CYR61 CCN a and the in CYR61 is to and the an is growth and growth protein CYR61 is in fibroblasts of during wound and in of of and the of a of growth and that during wound that the of CYR61 to integrin is the up-regulation of and in during cutaneous wound CYR61 the of growth an angiogenic factor and a and factor CYR61 the of matrix metalloproteinases 1 and to a in angiogenesis and matrix during wound angiogenesis and wound in a is that extracellular CYR61 of of that CYR61 and CCN to is to is of and CYR61 a of heparin-binding of CYR61 to in and of is that CYR61 integrin that adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans, adhesion to to in the of mediated through and integrin integrin a integrin in a cell been to cell adhesion and through integrin and through adhesion to is mediated through integrin through integrin CYR61 is in to and a in dermal of integrin CYR61 the to the cell adhesion CYR61 the and CYR61 a CYR61 cell adhesion to the CYR61, the a factor through integrin integrin CYR61 to cell in to cell adhesion and to CYR61 in mediated through integrin and adhesion of is mediated through integrin and cell of integrin to CYR61 an CCN of CYR61 and CCN the of integrin signaling in cell and that the and of of the angiogenic the of CYR61 is and fibroblasts is to CYR61 induces through integrin and enhances growth through integrin that CYR61 is a integrin that CYR61 integrin to and to the of the structural domains in of the CCN protein the of a that the of to a of the in a member of the CCN protein family, the is to of the in the domains to that a CCN protein the domains is of a of the protein a of to the is and cell adhesion that CCN in vivo the the CYR61 is adhesion is that is of adhesion is that is to CYR61 in to and to growth that the is the of has been to the that in the the has been to CYR61 is enhances the growth has been that CYR61 to growth is that the of and the of CYR61 and and through that CYR61 growth through integrin to that the cell and of CYR61 the and is the of integrin to cell and signaling mediated through integrin has been to of and signaling growth the that CYR61 enhances growth the is in of through integrin CYR61 has been to a of and in that CYR61 is a integrin mediates the of CYR61 in fibroblasts of protein that an and CYR61 CCN a and the in CYR61 is to and the an is growth and growth protein CYR61 is in fibroblasts of during wound and in of of and the of a of growth and that during wound that the of CYR61 to integrin is the up-regulation of and in during cutaneous wound CYR61 the of growth an angiogenic factor and a and factor CYR61 the of matrix metalloproteinases 1 and to a in angiogenesis and matrix during wound angiogenesis and wound in a is that extracellular CYR61 of of that CYR61 and CCN to is to is of and CYR61 a of heparin-binding of CYR61 to in and of is that CYR61 integrin that adhesion to CYR61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans, adhesion to to in the of mediated through and integrin integrin a integrin in a cell been to cell adhesion and through integrin and through adhesion to is mediated through integrin through integrin CYR61 is in to and a in dermal of integrin CYR61 the to the cell adhesion CYR61 the and CYR61 a CYR61 cell adhesion to the CYR61, the a factor through integrin integrin CYR61 to cell in to cell adhesion and to CYR61 in mediated through integrin and adhesion of is mediated through integrin and cell of integrin to CYR61 an CCN of CYR61 and CCN the of integrin signaling in cell and and and of the is the of an