The SH3 domain distinguishes the role of I-BAR proteins IRTKS and MIM in chemotactic response to serum.
The family of inverse BAR (I-BAR) domain proteins participates in a range of cellular processes associated with membrane dynamics and consists of five distinct members. Three of the I-BAR proteins, including insulin receptor tyrosine kinase substrate (IRTKS), contain an SH3 domain near their C-termini. Yet, the function of the SH3 domain of IRTKS remains uncharacterized. Here we report that in contrast to MIM, which is a prototype of I-BAR proteins and does not contain an SH3 domain, IRTKS promoted serum-induced cell migration along with enhanced phosphorylation of mitogen activated kinases Erk1/2 and p38, and activation of small GTPases Rac1 and Cdc42. In addition, cells overexpressing IRTKS exhibited an increased polarity characterized by elongated cytoplasm and extensive lamellipodia at leading edges. However, a mutant with deletion of the SH3 domain attenuated both cellular motility and p38 phosphorylation but had little effect on Erk1/2 phosphorylation. Also, a chimeric mutant in which the N-terminal portion of MIM is fused with the C-terminal IRTKS, including the SH3 domain, was able to promote chemotactic response to serum and cellular polarity. In contrast, a chimeric mutant in which the N-terminal IRTKS is fused with the C-terminal MIM failed to do so. Furthermore, treatment of cells with SB203580, a selective inhibitor of p38, also neutralized the effect of IRTKS on cell migration. These data indicate that the SH3 domain distinguishes the function of IRTKS in promoting cell migration and inducing signal transduction from those of SH3-less I-BAR proteins.
School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China; The Center for Vascular and Inflammatory Diseases and The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Lushen
L
Li
China-Japan Union Hospital of Jilin University, Changchun, 130031, China.
Hongyu
H
Liu
The Center for Vascular and Inflammatory Diseases and The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Shaneen S
SS
Baxter
School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
Ning
N
Gu
School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China. Electronic address: jimin@seu.edu.cn.
Min
M
Ji
The Center for Vascular and Inflammatory Diseases and The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: xzhan@som.umaryland.edu.
Xi
X
Zhan
D000818:Animals; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics / Q000502:physiology
C523100:BAIAP2L1 protein, human; C486778:MTSS1 protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; C107953:RAC1 protein, human; D011993:Recombinant Fusion Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
Cell migration; Cell morphology; IRTKS; MIM; SH3; Small GTPases; p38
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