Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling

Wendy M. Pruitt; Antoine E. Karnoub; A. Corinne Rakauskas; Michel Guipponi; Stylianos E. Antonarakis; Alexei Kurakin; Brian K. Kay; John Sondek; David P. Siderovski; Channing J. Der

doi:10.1016/S0167-4889(03)00002-8

Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling

Wendy M. Pruitt, Antoine E. Karnoub, A. Corinne Rakauskas, Michel Guipponi, Stylianos E. Antonarakis, Alexei Kurakin, Brian K. Kay, John Sondek, David P. Siderovski, Channing J. Der

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17 Scopus citations

Abstract

Intersectin-long (ITSN-L) contains the invariant Dbl homology (DH) and pleckstrin homology (PH) domain structure characteristic of the majority of Dbl family proteins. This strict domain topography suggests that the PH domain serves an essential, conserved function in the regulation of the intrinsic guanine nucleotide exchange activity of the DH domain. We evaluated the role of the PH domain in regulating the DH domain function of ITSN-L. Surprisingly, we found that the PH domain was dispensable for guanine nucleotide exchange activity on Cdc42 in vitro, yet the PH domain enhanced the ability of the DH domain to activate Cdc42 signaling in vivo. PH domains can interact with phosphoinositide substrates and products of phosphatidylinositol 3-kinase (PI3K). However, PI3K activation did not modulate ITSN-L DH domain function in vivo.

Original language	English
Pages (from-to)	61-68
Number of pages	8
Journal	Biochimica et Biophysica Acta - Molecular Cell Research
Volume	1640
Issue number	1
DOIs	https://doi.org/10.1016/S0167-4889(03)00002-8
State	Published - 7 Apr 2003

Keywords

Cdc42
Dbl family protein
Dbl homology domain
Phosphatidylinositol 3-kinase
Pleckstrin homology domain

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Pruitt, W. M., Karnoub, A. E., Rakauskas, A. C., Guipponi, M., Antonarakis, S. E., Kurakin, A., Kay, B. K., Sondek, J., Siderovski, D. P., & Der, C. J. (2003). Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling. Biochimica et Biophysica Acta - Molecular Cell Research, 1640(1), 61-68. https://doi.org/10.1016/S0167-4889(03)00002-8

@article{332499b9e7e14d9ba2bcd4088f43bc9e,

title = "Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling",

abstract = "Intersectin-long (ITSN-L) contains the invariant Dbl homology (DH) and pleckstrin homology (PH) domain structure characteristic of the majority of Dbl family proteins. This strict domain topography suggests that the PH domain serves an essential, conserved function in the regulation of the intrinsic guanine nucleotide exchange activity of the DH domain. We evaluated the role of the PH domain in regulating the DH domain function of ITSN-L. Surprisingly, we found that the PH domain was dispensable for guanine nucleotide exchange activity on Cdc42 in vitro, yet the PH domain enhanced the ability of the DH domain to activate Cdc42 signaling in vivo. PH domains can interact with phosphoinositide substrates and products of phosphatidylinositol 3-kinase (PI3K). However, PI3K activation did not modulate ITSN-L DH domain function in vivo.",

keywords = "Cdc42, Dbl family protein, Dbl homology domain, Phosphatidylinositol 3-kinase, Pleckstrin homology domain",

author = "Pruitt, {Wendy M.} and Karnoub, {Antoine E.} and Rakauskas, {A. Corinne} and Michel Guipponi and Antonarakis, {Stylianos E.} and Alexei Kurakin and Kay, {Brian K.} and John Sondek and Siderovski, {David P.} and Der, {Channing J.}",

note = "Funding Information: Our research was supported by grants from the National Institutes of Health to C.J.D. (CA63071) and J.S. (GM62299), the Pew Charitable Trusts to J.S., the Swiss Science National Foundation to S.E.A. and from the Leukemia and Lymphoma Society to B.K.K. W.M.P. is supported by a UNCF-Merck Postdoctoral Research Fellowship and D.P.S. is a Year 2000 Neuroscience Scholar of the EJLB Foundation. A.E.K. is a fellow of the Susan G. Komen Breast Cancer Foundation.",

year = "2003",

month = apr,

day = "7",

doi = "10.1016/S0167-4889(03)00002-8",

language = "English",

volume = "1640",

pages = "61--68",

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Pruitt, WM, Karnoub, AE, Rakauskas, AC, Guipponi, M, Antonarakis, SE, Kurakin, A, Kay, BK, Sondek, J, Siderovski, DP & Der, CJ 2003, 'Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling', Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1640, no. 1, pp. 61-68. https://doi.org/10.1016/S0167-4889(03)00002-8

TY - JOUR

T1 - Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling

AU - Pruitt, Wendy M.

AU - Karnoub, Antoine E.

AU - Rakauskas, A. Corinne

AU - Guipponi, Michel

AU - Antonarakis, Stylianos E.

AU - Kurakin, Alexei

AU - Kay, Brian K.

AU - Sondek, John

AU - Siderovski, David P.

AU - Der, Channing J.

N1 - Funding Information: Our research was supported by grants from the National Institutes of Health to C.J.D. (CA63071) and J.S. (GM62299), the Pew Charitable Trusts to J.S., the Swiss Science National Foundation to S.E.A. and from the Leukemia and Lymphoma Society to B.K.K. W.M.P. is supported by a UNCF-Merck Postdoctoral Research Fellowship and D.P.S. is a Year 2000 Neuroscience Scholar of the EJLB Foundation. A.E.K. is a fellow of the Susan G. Komen Breast Cancer Foundation.

PY - 2003/4/7

Y1 - 2003/4/7

N2 - Intersectin-long (ITSN-L) contains the invariant Dbl homology (DH) and pleckstrin homology (PH) domain structure characteristic of the majority of Dbl family proteins. This strict domain topography suggests that the PH domain serves an essential, conserved function in the regulation of the intrinsic guanine nucleotide exchange activity of the DH domain. We evaluated the role of the PH domain in regulating the DH domain function of ITSN-L. Surprisingly, we found that the PH domain was dispensable for guanine nucleotide exchange activity on Cdc42 in vitro, yet the PH domain enhanced the ability of the DH domain to activate Cdc42 signaling in vivo. PH domains can interact with phosphoinositide substrates and products of phosphatidylinositol 3-kinase (PI3K). However, PI3K activation did not modulate ITSN-L DH domain function in vivo.

AB - Intersectin-long (ITSN-L) contains the invariant Dbl homology (DH) and pleckstrin homology (PH) domain structure characteristic of the majority of Dbl family proteins. This strict domain topography suggests that the PH domain serves an essential, conserved function in the regulation of the intrinsic guanine nucleotide exchange activity of the DH domain. We evaluated the role of the PH domain in regulating the DH domain function of ITSN-L. Surprisingly, we found that the PH domain was dispensable for guanine nucleotide exchange activity on Cdc42 in vitro, yet the PH domain enhanced the ability of the DH domain to activate Cdc42 signaling in vivo. PH domains can interact with phosphoinositide substrates and products of phosphatidylinositol 3-kinase (PI3K). However, PI3K activation did not modulate ITSN-L DH domain function in vivo.

KW - Cdc42

KW - Dbl family protein

KW - Dbl homology domain

KW - Phosphatidylinositol 3-kinase

KW - Pleckstrin homology domain

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U2 - 10.1016/S0167-4889(03)00002-8

DO - 10.1016/S0167-4889(03)00002-8

M3 - Article

C2 - 12676355

AN - SCOPUS:0037424854

SN - 0167-4889

VL - 1640

SP - 61

EP - 68

JO - BBA - Molecular Cell Research

JF - BBA - Molecular Cell Research

IS - 1

ER -

Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling

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