IQGAP2 functions as a GTP-dependent effector protein in thrombin-induced platelet cytoskeletal reorganization.
Human blood platelets are anucleate cells whose response to extracellular stimuli results in actin cytoskeleton rearrangements, thereby providing the critical initial step in the regulation of hemostasis. The serine protease alpha-thrombin, known to activate platelets by cleavage of a family of protease-activated receptors (PARs), is the most potent physiologic activator of human platelets, though downstream effector proteins uniquely linked to platelet cytoskeletal actin polymerization remain largely uncharacterized. The gene encoding the putative rac1/cdc42 effector protein IQGAP2 was identified within the PAR gene cluster at 5q13, flanked telomeric by PAR1 and encompassing PAR3. Immunofluorescence microscopy demonstrated IQGAP2 expression in filopodial extensions of activated platelets and colocalized with F-actin in lamellipodia and filopodia of IQGAP2-transfected COS1 cells. Platelet activation by alpha-thrombin, but not saturating concentrations of fibrillar collagen or adenosine 5'-diphosphate, uniquely assemble an IQGAP2/arp2/3-actin cytoplasmic complex, an association regulated by guanosine triphosphate rac1 ([GTP]rac1) but not by [GTP]cdc42. Likewise, only thrombin-activated platelets resulted in rapid translocation of IQGAP2 to the platelet cytoskeleton. These observations identify a physiologic scaffolding function for IQGAP2 and establish the presence of a functional genomic unit in humans uniquely evolved to regulate thrombin-induced platelet cytoskeletal actin reorganization.
Schmidt
Valentina A
VA
Department of Medicine and the Program in Genetics, State University of New York, Stony Brook, 11794, USA.
Scudder
Lesley
L
Devoe
Craig E
CE
Bernards
André
A
Cupit
Lisa D
LD
Bahou
Wadie F
WF
D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000648:ultrastructure*; D019556:COS Cells / Q000737:chemistry / Q000648:ultrastructure; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002522:Chlorocebus aethiops; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003094:Collagen / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008856:Microscopy, Fluorescence; D020161:Physical Chromosome Mapping; D015539:Platelet Activation / Q000187:drug effects*; D011554:Pseudopodia / Q000737:chemistry; D013917:Thrombin / Q000494:pharmacology*; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000502:physiology; D020703:ras GTPase-Activating Proteins
C495926:ACTR2 protein, human; C495928:ACTR3 protein, human; D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C101002:IQGAP2 protein, human; D046911:Macromolecular Substances; D020703:ras GTPase-Activating Proteins; D000244:Adenosine Diphosphate; D006160:Guanosine Triphosphate; D003094:Collagen; D013917:Thrombin; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein