HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 44, 32093-32105, November 2, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/44/32093    most recent M703517200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Manna, D. Articles by Cho, W. Search for Related Content PubMed PubMed Citation Articles by Manna, D. Articles by Cho, W. Social Bookmarking                      What's this?

Mechanistic Basis of Differential Cellular Responses of Phosphatidylinositol 3,4-Bisphosphate- and Phosphatidylinositol 3,4,5-Trisphosphate-binding Pleckstrin Homology Domains^*

Debasis Manna, Alexandra Albanese, Wei Sun Park, and Wonhwa Cho¹

From the Department of Chemistry, University of Illinois, Chicago, Illinois 60607 and the Department of Chemical and Systems Biology, Stanford University Medical Center, Stanford, California 94305-5439

Phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P₂) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P₃) are lipid second messengers that regulate various cellular processes by recruiting a wide range of downstream effector proteins to membranes. Several pleckstrin homology (PH) domains have been reported to interact with PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃. To understand how these PH domains differentially respond to PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃ signals, we quantitatively determined the PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃ binding properties of several PH domains, including Akt, ARNO, Btk, DAPP1, Grp1, and C-terminal TAPP1 PH domains by surface plasmon resonance and monolayer penetration analyses. The measurements revealed that these PH domains have significant different phosphoinositide specificities and affinities. Btk-PH and TAPP1-PH showed genuine PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ specificities, respectively, whereas other PH domains exhibited less pronounced specificities. Also, the PH domains showed different degrees of membrane penetration, which greatly affected the kinetics of their membrane dissociation. Mutational studies showed that the presence of two proximal hydrophobic residues on the membrane-binding surface of the PH domain is important for membrane penetration and sustained membrane residence. When NIH 3T3 cells were stimulated with platelet-derived growth factor to generate PtdIns(3,4,5)P₃, reversible translocation of Btk-PH, Grp1-PH, ARNO-PH, DAPP1-PH, and its L177A mutant to the plasma membrane was consistent with their in vitro membrane binding properties. Collectively, these studies provide new insight into how various PH domains would differentially respond to cellular PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃ signals.

Received for publication, April 26, 2007 , and in revised form, August 6, 2007.

^* This work was supported by National Institutes of Health Grant GM68849. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Chemistry (M/C 111), University of Illinois, 845 West Taylor St., Chicago, IL 60607-7061. Tel.: 312-996-4883; Fax: 312-996-2183; E-mail: wcho{at}uic.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. Manna, N. Bhardwaj, M. S. Vora, R. V. Stahelin, H. Lu, and W. Cho Differential Roles of Phosphatidylserine, PtdIns(4,5)P2, and PtdIns(3,4,5)P3 in Plasma Membrane Targeting of C2 Domains: MOLECULAR DYNAMICS SIMULATION, MEMBRANE BINDING, AND CELL TRANSLOCATION STUDIES OF THE PKC{alpha} C2 Domain J. Biol. Chem., September 19, 2008; 283(38): 26047 - 26058. [Abstract] [Full Text] [PDF]

				J. He, R. M. Haney, M. Vora, V. V. Verkhusha, R. V. Stahelin, and T. G. Kutateladze Molecular mechanism of membrane targeting by the GRP1 PH domain,boxs J. Lipid Res., August 1, 2008; 49(8): 1807 - 1815. [Abstract] [Full Text] [PDF]