From Src Homology Domains to Other Signaling Modules: Proposal of the `Protein Recognition Code'
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Paxillin: a Focal Adhesion-Associated Adaptor Protein
Oncogene (2001) 20, 6459 ± 6472 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Paxillin: a focal adhesion-associated adaptor protein Michael D Schaller*,1 1Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center and Comprehensive Center for In¯ammatory Disorders, University of North Carolina, Chapel Hill, North Carolina, NC 27599, USA Paxillin is a focal adhesion-associated, phosphotyrosine- The molecular cloning of paxillin revealed a number containing protein that may play a role in several of motifs that are now known to function in mediating signaling pathways. Paxillin contains a number of motifs protein ± protein interactions (see Figure 1) (Turner that mediate protein ± protein interactions, including LD and Miller, 1994; Salgia et al., 1995a). The N-terminal motifs, LIM domains, an SH3 domain-binding site and half of paxillin contains a proline-rich region that SH2 domain-binding sites. These motifs serve as docking could serve as an SH3 domain-binding site. Several sites for cytoskeletal proteins, tyrosine kinases, serine/ tyrosine residues conforming to SH2 domain binding threonine kinases, GTPase activating proteins and other sites were also noted. In addition, the N-terminal adaptor proteins that recruit additional enzymes into domain of paxillin contains ®ve copies of a peptide complex with paxillin. Thus paxillin itself serves as a sequence, called the LD motif, which are now known docking protein to recruit signaling molecules to a to function as binding sites for other proteins (see speci®c cellular compartment, the focal adhesions, and/ Table 1) (Brown et al., 1998a). The C-terminal half of or to recruit speci®c combinations of signaling molecules paxillin is comprised of four LIM domains, which are into a complex to coordinate downstream signaling. -
Interactions of Cbl with Grb2 and Phosphatidylinositol 3'-Kinase in Activated Jurkat Cells
University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 1995-07-01 Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells Herman Meisner University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Life Sciences Commons, and the Medicine and Health Sciences Commons Repository Citation Meisner H, Conway BR, Hartley DA, Czech MP. (1995). Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells. Open Access Articles. Retrieved from https://escholarship.umassmed.edu/oapubs/1457 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. MOLECULAR AND CELLULAR BIOLOGY, July 1995, p. 3571–3578 Vol. 15, No. 7 0270-7306/95/$04.0010 Copyright q 1995, American Society for Microbiology Interactions of Cbl with Grb2 and Phosphatidylinositol 39-Kinase in Activated Jurkat Cells HERMAN MEISNER, BRUCE R. CONWAY, DAVID HARTLEY, AND MICHAEL P. CZECH* Program in Molecular Medicine and Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 Received 28 December 1994/Returned for modification 20 February 1995/Accepted 31 March 1995 T-cell receptor (TCR) cross-linking increases tyrosine phosphorylation of multiple proteins, only a few of which have been identified. One of the most rapidly tyrosine-phosphorylated polypeptides is the 120-kDa product of the proto-oncogene c-cbl, a cytosolic and cytoskeletal protein containing multiple proline-rich motifs that are potential binding sites for proteins containing Src homology 3 (SH3) domains. -
Cell Activation , Is Required for T Lck SH2 Domain of P56 Lad, An
Lad, an Adapter Protein Interacting with the SH2 Domain of p56 lck, Is Required for T Cell Activation This information is current as Young Bong Choi, Chan Ki Kim and Yungdae Yun of September 27, 2021. J Immunol 1999; 163:5242-5249; ; http://www.jimmunol.org/content/163/10/5242 Downloaded from References This article cites 54 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/163/10/5242.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Lad, an Adapter Protein Interacting with the SH2 Domain of p56lck, Is Required for T Cell Activation1,2 Young Bong Choi,*† Chan Ki Kim,* and Yungdae Yun3*† T cell-specific Src family tyrosine kinase, p56lck, plays crucial roles in T cell differentiation, activation, and proliferation. These multiple functions of p56lck are believed to be conducted through the protein-protein interactions with various cellular signaling proteins. -
The PX Domain Protein Interaction Network in Yeast
The PX domain protein interaction network in yeast Zur Erlangung des akademischen Grades eines DOKTORS DER NATURWISSENSCHAFTEN (Dr. rer. nat.) der Fakultät für Chemie und Biowissenschaften der Universität Karlsruhe (TH) vorgelegte DISSERTATION von Dipl. Biol. Carolina S. Müller aus Buenos Aires Dekan: Prof. Dr. Manfred Kappes Referent: Dr. Nils Johnsson Korreferent: HD. Dr. Adam Bertl Tag der mündlichen Prüfung: 17.02.2005 I dedicate this work to my Parents and Alex TABLE OF CONTENTS Table of contents Introduction 1 Yeast as a model organism in proteome analysis 1 Protein-protein interactions 2 Protein Domains in Yeast 3 Classification of protein interaction domains 3 Phosphoinositides 5 Function 5 Structure 5 Biochemistry 6 Localization 7 Lipid Binding Domains 8 The PX domain 10 Function of PX domain containing proteins 10 PX domain structure and PI binding affinities 10 Yeast PX domain containing proteins 13 PX domain and protein-protein interactions 13 Lipid binding domains and protein-protein interactions 14 The PX-only proteins Grd19p and Ypt35p and their phenotypes 15 Aim of my PhD work 16 Project outline 16 Searching for interacting partners 16 Confirmation of obtained interactions via a 16 second independent method Mapping the interacting region 16 The Two-Hybrid System 17 Definition 17 Basic Principle of the classical Yeast-Two Hybrid System 17 Peptide Synthesis 18 SPOT synthesis technique 18 Analysis of protein- peptide contact sites based on SPOT synthesis 19 TABLE OF CONTENTS Experimental procedures 21 Yeast two-hybrid assay -
PDZ Domain from Dishevelled — a Specificity Study Katarzyna Śmietana, Agnieszka Mateja, Artur Krężel and Jacek Otlewski*
Vol. 58, No. 2/2011 243–249 on-line at: www.actabp.pl Regular paper PDZ domain from Dishevelled — a specificity study Katarzyna Śmietana, Agnieszka Mateja, Artur Krężel and Jacek Otlewski* Faculty of Biotechnology, Department of Protein Engineering, University of Wrocław, Wrocław, Poland Intracellular signaling cascades induced by Wnt proteins play a key role in developmental processes and are im- It is still unclear what mechanism governs the activa- plicated in cancerogenesis. It is still unclear how the cell tion of the correct Wnt signaling branch. Dishevelled determines which of the three possible Wnt response (Dvl) proteins, the last shared link of the canonical and mechanisms should be activated, but the decision proc- non-canonical pathways, most likely play a key regulatory ess is most likely dependent on Dishevelled proteins. role in the signal distribution process (Habas & Dawid, Dishevelled family members interact with many diverse 2005; Itoh et al., 2005; Leonard & Ettensohn, 2007). This targets, however, molecular mechanisms underlying notion is further supported by the fact that the multi- these binding events have not been comprehensively tude of Dvl binding partners includes proteins that re- described so far. Here, we investigated the specificity of lay signaling to β-catenin pathways (axin (Li et al., 1999; the PDZ domain from human Dishevelled-2 using C-ter- Wharton, 2003), GBP/Frat (Li et al., 1999)), PCP (Rac1 minal phage display, which led us to identification of a (Fanto et al., 2000), Daam1 (Habas et al., 2001), strabis- 2+ leucine-rich binding motif strongly resembling the con- mus (Bastock et al., 2003)) and Ca (Gαo/Gαt (Liu et al., sensus sequence of a nuclear export signal. -
Insulin Receptor Tyrosine Kinase Substrate Links the E. Coli O157:H7
Insulin receptor tyrosine kinase substrate links the E. coli O157:H7 actin assembly effectors Tir and EspFU during pedestal formation Didier Vingadassaloma, Arunas Kazlauskasb, Brian Skehana, Hui-Chun Chengc, Loranne Magouna, Douglas Robbinsa, Michael K. Rosenc, Kalle Sakselab, and John M. Leonga,1 aDepartment of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655; bDepartment of Virology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital, FIN-00014, Helsinki, Finland; and cDepartment of Biochemistry and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Edited by R. John Collier, Harvard Medical School, Boston, MA, and approved March 2, 2009 (received for review September 12, 2008) Enterohemorrhagic Escherichia coli O157:H7 translocates 2 effec- host cell plasma membrane with N- and C-terminal intracellular tors to trigger localized actin assembly in mammalian cells, result- domains and a central extracellular domain that binds to the ing in filamentous actin ‘‘pedestals.’’ One effector, the translocated bacterial outer membrane protein intimin. Clustering of Tir in the intimin receptor (Tir), is localized in the plasma membrane and host cell membrane upon intimin binding initiates a signaling clustered upon binding the bacterial outer membrane protein cascade, ultimately leading to actin pedestal formation. intimin. The second, the proline-rich effector EspFU (aka TccP) For the canonical EPEC strain, serotype O127:H6, Tir is the activates the actin nucleation-promoting factor WASP/N-WASP, only translocated effector required for pedestal formation, and and is recruited to sites of bacterial attachment by a mechanism after becoming phosphorylated on tyrosine residue 474 (Y474) dependent on an Asn-Pro-Tyr (NPY458) sequence in the Tir C- by mammalian kinases, recruits the SH2 domain-containing terminal cytoplasmic domain. -
Direct Interaction Between Calmodulin and the Grb7 RA-PH Domain
International Journal of Molecular Sciences Article Direct Interaction between Calmodulin and the Grb7 RA-PH Domain Gabrielle M. Watson and Jacqueline A. Wilce * Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton VIC 3800, Australia; [email protected] * Correspondence: [email protected]; Tel.: +613-9902-9226; Fax: +613-9902-9500 Received: 7 January 2020; Accepted: 15 February 2020; Published: 17 February 2020 Abstract: Grb7 is a signalling adapter protein that engages activated receptor tyrosine kinases at cellular membranes to effect downstream pathways of cell migration, proliferation and survival. Grb7’s cellular location was shown to be regulated by the small calcium binding protein calmodulin (CaM). While evidence for a Grb7/CaM interaction is compelling, a direct interaction between CaM and purified Grb7 has not been demonstrated and quantitated. In this study we sought to determine this, and prepared pure full-length Grb7, as well as its RA-PH and SH2 subdomains, and tested for CaM binding using surface plasmon resonance. We report a direct interaction between full-length Grb7 and CaM that occurs in a calcium dependent manner. While no binding was observed to the SH2 domain alone, we observed a high micromolar affinity interaction between the Grb7 RA-PH domain and CaM, suggesting that the Grb7/CaM interaction is mediated through this region of Grb7. Together, our data support the model of a CaM interaction with Grb7 via its RA-PH domain. Keywords: Grb7; Calmodulin; RA-PH domain; SH2 domain; SPR 1. Introduction Growth receptor bound 7 (Grb7) protein is a cytoplasmic adapter protein that couples activated tyrosine kinase receptors to a nexus of downstream proliferative, migratory and survival signalling pathways [1,2]. -
Phosphotyrosine Signaling: Evolving a New Cellular Communication System
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Leading Edge Essay Phosphotyrosine Signaling: Evolving a New Cellular Communication System Wendell A. Lim1,2,* and Tony Pawson3,4,* 1Howard Hughes Medical Institute 2Department of Cellular and Molecular Pharmacology University of California, San Francisco, San Francisco, CA 94158, USA 3Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada 4Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada *Correspondence: [email protected] (W.A.L.), [email protected] (T.P.) DOI 10.1016/j.cell.2010.08.023 Tyrosine phosphorylation controls many cellular functions. Yet the three-part toolkit that regulates phosphotyrosine signaling—tyrosine kinases, phosphotyrosine phosphatases, and Src Homology 2 (SH2) domains—is a relatively new innovation. Genomic analyses reveal how this revolutionary signaling system may have originated and why it rapidly became critical to metazoans. Throughout human history, new technolo- (TyrK) phosphorylate specific target with an evolutionary process? Proteins gies and technological platforms have tyrosine residues, phosphotyrosine phos- that bind or remove a posttranslational constantly been invented. Only a small phatases (PTP) remove the phosphates, modification would seem useless without fraction of these technologies go on to and Src Homology 2 (SH2) domains an enzyme to generate the modification be widely adopted, but these can recognize the modifications (Pawson and, in principle, would not provide ultimately have transformational conse- 1995). Together, these three modules a fitness advantage leading to its retention quences. In the evolutionary history of form the ‘‘writer,’’ ‘‘eraser,’’ and ‘‘reader’’ and spread. -
Insight Into the Brain-Specific Alpha Isoform of the Scaffold Protein SH2B1 and Its Rare Obesity-Associated Variants
Insight into the Brain-Specific Alpha Isoform of the Scaffold Protein SH2B1 and its Rare Obesity-Associated Variants By Ray Morris Joe A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Cellular and Molecular Biology) in the University of Michigan 2017 Doctoral Committee: Professor Christin Carter-Su, Chair Professor Ken Inoki Professor Benjamin L. Margolis Professor Donna M. Martin Professor Martin G. Myers © Ray Morris Joe ORCID: 0000-0001-7716-2874 [email protected] All rights reserved 2017 Acknowledgements I’d like to thank my mentor, Christin Carter-Su, for providing me a second opportunity and taking a chance on me after my leave of absence without hesitation. It is an honor to have a mentor guide me through the many challenges I have faced as a graduate student. She has taught me to find passion in my profession, and to strive to push through obstacles and find ways to reach my goals. In addition, she has given me insight to find a balance between work and life by giving me freedom to independently perform my research as well as stories on family and child-rearing. Throughout the many countless days and nights writing grants, manuscripts, and analyzing/interpreting data, it was wonderful to share our past cultural identities with one another. I look forward to having Christy as a mentor, colleague, and friend for all my future endeavors I have after I leave her laboratory. I want to thank my thesis committee, Ken Inoki, Ben Margolis, Donna Martin, and Martin Myers for the numerous insights for my scientific training. -
A Web Resource for Structure Based Analysis of Human PDZ-Mediated Interaction Networks Neetu Sain and Debasisa Mohanty*
Sain and Mohanty Biology Direct (2016) 11:48 DOI 10.1186/s13062-016-0151-4 RESEARCH Open Access modPDZpep: a web resource for structure based analysis of human PDZ-mediated interaction networks Neetu Sain and Debasisa Mohanty* Abstract Background: PDZ domains recognize short sequence stretches usually present in C-terminal of their interaction partners. Because of the involvement of PDZ domains in many important biological processes, several attempts have been made for developing bioinformatics tools for genome-wide identification of PDZ interaction networks. Currently available tools for prediction of interaction partners of PDZ domains utilize machine learning approach. Since, they have been trained using experimental substrate specificity data for specific PDZ families, their applicability is limited to PDZ families closely related to the training set. These tools also do not allow analysis of PDZ-peptide interaction interfaces. Results: We have used a structure based approach to develop modPDZpep, a program to predict the interaction partners of human PDZ domains and analyze structural details of PDZ interaction interfaces. modPDZpep predicts interaction partners by using structural models of PDZ-peptide complexes and evaluating binding energy scores using residue based statistical pair potentials. Since, it does not require training using experimental data on peptide binding affinity, it can predict substrates for diverse PDZ families. Because of the use of simple scoring function for binding energy, it is also fast enough for genome scale structure based analysis of PDZ interaction networks. Benchmarking using artificial as well as real negative datasets indicates good predictive power with ROC-AUC values in the range of 0.7 to 0.9 for a large number of human PDZ domains. -
The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation
ANRV306-IY25-19 ARI 11 February 2007 12:51 The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation Hyun Ho Park,1 Yu-Chih Lo,1 Su-Chang Lin,1 Liwei Wang,1 Jin Kuk Yang,1,2 and Hao Wu1 1Department of Biochemistry, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021; email: [email protected] 2Department of Chemistry, Soongsil University, Seoul 156-743, Korea Annu. Rev. Immunol. 2007. 25:561–86 Key Words First published online as a Review in Advance on death domain (DD), death effector domain (DED), tandem DED, January 2, 2007 caspase recruitment domain (CARD), pyrin domain (PYD), crystal The Annual Review of Immunology is online at structure, NMR structure immunol.annualreviews.org This article’s doi: Abstract 10.1146/annurev.immunol.25.022106.141656 The death domain (DD) superfamily comprising the death domain Copyright c 2007 by Annual Reviews. (DD) subfamily, the death effector domain (DED) subfamily, the Annu. Rev. Immunol. 2007.25:561-586. Downloaded from arjournals.annualreviews.org by CORNELL UNIVERSITY MEDICAL COLLEGE on 03/29/07. For personal use only. All rights reserved caspase recruitment domain (CARD) subfamily, and the pyrin do- 0732-0582/07/0423-0561$20.00 main (PYD) subfamily is one of the largest domain superfamilies. By mediating homotypic interactions within each domain subfam- ily, these proteins play important roles in the assembly and activation of apoptotic and inflammatory complexes. In this chapter, we review the molecular complexes assembled by these proteins, the structural and biochemical features of these domains, and the molecular in- teractions mediated by them. -
Meltrin a Cytoplasmic Domain Interacts with SH3 Domains of Src and Grb2 and Is Phosphorylated by V-Src
Oncogene (2000) 19, 5842 ± 5850 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Meltrin a cytoplasmic domain interacts with SH3 domains of Src and Grb2 and is phosphorylated by v-Src Akiko Suzuki1, Nae Kadota1, Tomokazu Hara1, Yoshiko Nakagami1, Toshiaki Izumi1, Tadaomi Takenawa2, Hisataka Sabe3 and Takeshi Endo*,1 1Department of Biology, Faculty of Science, Chiba University, Yayoicho, Inageku, Chiba, Chiba 263-8522, Japan; 2Department of Biochemistry, Institute of Medical Science, University of Tokyo, Shirokanedai, Minatoku, Tokyo 108-8639, Japan; 3Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan Meltrin a/ADAM12 is a member of the ADAM/MDC receptor tyrosine kinases, tyrosine kinase-coupled family proteins characterized by the presence of cytokine receptors, TGF-b family receptor serine/ metalloprotease and disintegrin domains. This protein threonine kinases, and seven-pass G protein-coupled also contains a single transmembrane domain and a receptors. Integrins and cadherins not only serve as relatively long cytoplasmic domain containing several transmembrane adhesion molecules but also participate proline-rich sequences. These sequences are compatible in intracellular and extracellular signaling (Schwartz et with the consensus sequences for binding the Src al., 1995; Ben-Ze'ev, 1997; Yamada and Geiger, 1997). homology 3 (SH3) domains. To determine whether the ADAM/MDC family proteins have emerged as proline-rich sequences interact with SH3 domains in candidate molecules for proteolytic processing, cell ± several proteins, binding of recombinant SH3 domains to cell attachment, and cell fusion (Wolfsberg et al., 1995; the meltrin a cytoplasmic domain was analysed by pull- Wolfsberg and White, 1996; Huovila et al., 1996; Black down assays.