The association of cortactin with profilin-1 is critical for smooth muscle contraction.
Profilin-1 (Pfn-1) is an actin-regulatory protein that has a role in modulating smooth muscle contraction. However, the mechanisms that regulate Pfn-1 in smooth muscle are not fully understood. Here, stimulation with acetylcholine induced an increase in the association of the adapter protein cortactin with Pfn-1 in smooth muscle cells/tissues. Furthermore, disruption of the protein/protein interaction by a cell-permeable peptide (CTTN-I peptide) attenuated actin polymerization and smooth muscle contraction without affecting myosin light chain phosphorylation at Ser-19. Knockdown of cortactin by lentivirus-mediated RNAi also diminished actin polymerization and smooth muscle force development. However, cortactin knockdown did not affect myosin activation. In addition, cortactin phosphorylation has been implicated in nonmuscle cell migration. In this study, acetylcholine stimulation induced cortactin phosphorylation at Tyr-421 in smooth muscle cells. Phenylalanine substitution at this position impaired cortactin/Pfn-1 interaction in response to contractile activation. c-Abl is a tyrosine kinase that is necessary for actin dynamics and contraction in smooth muscle. Here, c-Abl silencing inhibited the agonist-induced cortactin phosphorylation and the association of cortactin with Pfn-1. Finally, treatment with CTTN-I peptide reduced airway resistance and smooth muscle hyperreactivity in a murine model of asthma. These results suggest that the interaction of cortactin with Pfn-1 plays a pivotal role in regulating actin dynamics, smooth muscle contraction, and airway hyperresponsiveness in asthma. The association of cortactin with Pfn-1 is regulated by c-Abl-mediated cortactin phosphorylation.
From the Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208.
Ruping
R
Wang
From the Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208.
Rachel A
RA
Cleary
From the Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208.
Tao
T
Wang
From the Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208.
Jia
J
Li
From the Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208 tangd@mail.amc.edu.
Dale D
DD
Tang
D000109:Acetylcholine / Q000494:pharmacology; D000199:Actins / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051356:Cortactin / Q000737:chemistry / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051304:Profilins / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
C513733:ABI1 protein, human; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C495868:CTTN protein, human; D051356:Cortactin; D003598:Cytoskeletal Proteins; D010446:Peptide Fragments; D051304:Profilins; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl; D000109:Acetylcholine
Actin; Adapter Protein; Contraction; Cytoskeleton; Excitation-Contraction Coupling; Protein Phosphorylation; Smooth Muscle