Gelsolin binding and cellular presentation of lysophosphatidic acid.
Lysophosphatidic acid (LPA) in biological fluids binds to serum albumin and other proteins that enhance its effects on cellular functions. The actin-severing protein gelsolin binds LPA with an affinity (K(d) = 6 nm) similar to that of the G protein-coupled LPA receptors encoded by endothelial differentiation genes 2, 4, and 7 (Edg-2, -4, and -7 receptors) and greater than that of serum albumin (K(d) = 360 nm). At concentrations of 10% or less of that in plasma, which are observed in fluids of injured tissues, purified and recombinant gelsolin augment LPA stimulation of nuclear signals and protein synthesis in rat cardiac myocytes (RCMs) that express Edg-2 and -4 receptors. At concentrations of 20% or more of that in plasma, gelsolin suppresses LPA stimulation of RCMs. The lack of effect of gelsolin on RCM responses to monoclonal anti-Edg-4 receptor antibody plus a phorbol ester without LPA attests to its specificity for LPA delivery and the absence of post-receptor effects. Inhibition of gelsolin binding and cellular delivery of LPA by l-alpha-phosphatidylinositol-4,5-bisphosphate (PIP2) and peptides constituting the two PIP2 binding domains of gelsolin suggests competition between LPA and PIP2 for the same sites. Thus, delivery of LPA to RCMs is affinity-coupled to Edg receptors by gelsolin in a PIP2-regulated process.
Goetzl
E J
EJ
Departments of Medicine and Microbiology-Immunology, University of California, San Francisco, California 94143-0711, USA. egoetzl@itsa.ucsf.edu
Lee
H
H
Azuma
T
T
Stossel
T P
TP
Turck
C W
CW
Karliner
J S
JS
D000595:Amino Acid Sequence; D000818:Animals; D018260:Gelsolin / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000378:metabolism; D015398:Signal Transduction
D018260:Gelsolin; D008246:Lysophospholipids; D012710:Serum Albumin, Bovine