Synthetic D-amino acid peptide inhibits tumor cell motility on laminin-5.
Cell motility is partially dependent on interactions between the integrins and the extracellular matrix. Our previous studies have identified synthetic D-amino acid cell adhesion peptides using a combinatorial screening approach. In this study, we demonstrate that HYD1 (kikmviswkg) completely blocks random haptotactic migration and inhibits invasion of prostate carcinoma cells on laminin-5. This effect is adhesion independent and reversible. The inhibition of migration by HYD1 involves a dramatic remodeling of the actin cytoskeleton resulting in increased stress fiber formation and actin colocalization with cortactin at the cell membrane. HYD1 interacts with alpha6beta1 (not alpha6beta4) and alpha3beta1 integrins and surprisingly elevates laminin-5-dependent intracellular signals including focal adhesion kinase, mitogen-activated protein kinase kinase and extracellular signal-regulated kinase. HYD1 does not contain a previously characterized binding sequence for integrins. A scrambled derivative of HYD1, called HYDS (wiksmkivkg), does not interact with the alpha6 or alpha3 integrin subunits and is not biologically active. Taken together, these results indicate that HYD1 is a biologically active integrin-targeting peptide that reversibly inhibits tumor cell migration on laminin-5 and uncouples phosphotyrosine signaling from cytoskeletal-dependent migration.
Department of Cell Biology and Anatomy, The University of Arizona, Tucson, AZ 85724, USA.
Thomas C
TC
Sroka
Michael E
ME
Pennington
Anne E
AE
Cress
D000199:Actins / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000378:metabolism; D008297:Male; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D000097794:Kalinin
D000199:Actins; D000596:Amino Acids; D015815:Cell Adhesion Molecules; D039201:Integrin alpha3beta1; D039121:Integrin alpha6beta1; D009842:Oligopeptides; D010455:Peptides; D000097794:Kalinin; C546443:lysyl-isoleucyl-lysyl-methionyl-valyl-isoleucyl-seryl-tryptophyl-lysyl-glycine