Cell-surface transglutaminase undergoes internalization and lysosomal degradation: an essential role for LRP1.
Tissue transglutaminase functions as a protein crosslinking enzyme and an integrin-binding adhesion co-receptor for fibronectin on the cell surface. These activities of transglutaminase and the involvement of this protein in cell-matrix adhesion, integrin-mediated signaling, cell migration and matrix organization suggest a precise and efficient control of its cell-surface expression. We report a novel mechanism of regulation of surface transglutaminase through internalization and subsequent lysosomal degradation. Constitutive endocytosis of cell-surface transglutaminase depends on plasma membrane cholesterol and the activity of dynamin-2, and involves both clathrin-coated pits and lipid rafts or caveolae. Furthermore, the key matrix ligands of transglutaminase, fibronectin and platelet-derived growth factor, promote its endocytosis from the cell surface. Our results also indicate that transglutaminase interacts in vitro and on the cell surface with the major endocytic receptor, low-density lipoprotein receptor-related protein 1, and demonstrate the requirement for this receptor in the endocytosis of transglutaminase. Finally, a deficiency of this endocytic receptor or blockade of endo-lysosomal function upregulate transglutaminase expression on the cell surface, leading to increased cell adhesion and matrix crosslinking. These findings characterize a previously unknown pathway of transglutaminase internalization and degradation that might be crucial for regulation of its adhesive and signaling functions on the cell surface and reveal a novel functional link between cell-matrix adhesion and endocytosis.
Zemskov
Evgeny A
EA
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Mikhailenko
Irina
I
Strickland
Dudley K
DK
Belkin
Alexey M
AM
D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D034285:Dynamin II / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D019204:GTP-Binding Proteins; D006801:Humans; D016023:Integrins / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008247:Lysosomes / Q000201:enzymology*; D021962:Membrane Microdomains / Q000201:enzymology*; D051379:Mice; D041681:NIH 3T3 Cells; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011973:Receptors, LDL / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D011503:Transglutaminases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D005353:Fibronectins; D016023:Integrins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D002784:Cholesterol; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D034285:Dynamin II