Integrin α6 cleavage: A novel modification to modulate cell migration

Sangita C. Pawar, Manolis C. Demetriou, Raymond B. Nagle, G. Tim Bowden, Anne E. Cress

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Integrins play a major role in cell adhesion and migration. Previous work reported that a cleaved form of integrin α6 (α6p) was detected in invasive human prostate cancer tissue, absent in normal prostate tissue and was produced by urokinase-type Plasminogen Activator (uPA) in a plasmin-independent manner. Using site-directed mutagenesis we identified amino acid residues R594 and R595, located in the "stalk" region of integrin α6, as essential for cleavage. The cleavage site is located on the extracellular region of the protein between the β-barrel domain and the thigh domain. Prostate cancer cells (PC3N) were stably transfected to overexpress the cleavable, wild-type (PC3N-α6-WT) or the non-cleavable form of integrin α6 (PC3N-α6-RR). The number of cells invading laminin 111- and laminin 332-coated filters by PC3N-α6-WT cells increased by threefold as compared to PC3N-α6-RR cells. Plasminogen activator inhibitor-1 (PAI-1) reduced the invasion of PC3N-α6-WT cells by approximately 42% through laminin 332-coated filters and plasmin inhibitor aprotinin had no significant effect. Linear cell migration increased production of integrin α6p in the PC3N-α6-WT cells and not in the PC3N-α6-RR cells and 32% of the PC3N-α6-WT cells migrated on laminin 111 in the linear migration assay as compared to the 5% PC3N-α6-RR cells. These data taken together suggest that the uPA-mediated cell surface cleavage of the α6 integrin extracellular domain is involved in tumor cell invasion and migration on laminin.

Original languageEnglish (US)
Pages (from-to)1080-1089
Number of pages10
JournalExperimental Cell Research
Volume313
Issue number6
DOIs
StatePublished - Apr 1 2007

Keywords

  • Cleavage
  • ECM
  • Integrin α6
  • Laminin
  • Migration
  • Prostate cancer
  • Urokinase
  • uPA

ASJC Scopus subject areas

  • Cell Biology

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