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Stevan R Hubbard

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Stevan R Hubbard, Ph.D.

Professor; Coord Structural Biology Program
Department of Biochemistry and Molecular Pharmacology and Structural Biology

Contact Info

Address
540 First Avenue
Floor 3 Room Lab 14
Skirball Institute
New York, NY 10016

Phone: 212-263-8938
Fax: 212-263-8951
Email: Stevan.Hubbard@med.nyu.edu

Web:	Hubbard Lab Website

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Education

— Dr. Hubbard was a Postdoctoral Research Scientist in the Department of Biochemistry and Molecular Biophysics, Columbia University, PostDoctoral Training
1988 — Dr. Hubbard obtained his Ph.D. in Applied Physics from Stanford University, Graduate Education

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Research Summary

Many important cellular signaling cascades are initiated at the cell surface by the binding of a polypeptide ligand to a transmembrane receptor possessing intrinsic tyrosine kinase activity in its cytoplasmic domain. The receptor tyrosine kinase (RTK) family includes, among others, the insulin receptor, insulin-like growth factor-1 (IGF1) receptor, epidermal growth factor receptor, fibroblast growth factor receptor and MuSK, the receptor for agrin. Ligand binding induces receptor oligomerization (growth factor receptors) or a conformational change within the receptor (insulin/IGF1 receptor), leading to autophosphorylation of specific tyrosine residues in the cytoplasmic domains of the receptors. Tyrosine autophosphorylation stimulates receptor catalytic activity and generates recruitment sites for downstream signaling proteins. RTKs are critical components in signal transduction pathways that mediate cell proliferation, differentiation, migration and metabolism, and are active during organismal development and adult homeostasis. RTKs also play primary roles in the onset or progression of pathological conditions such as diabetic retinopathy, atherosclerosis and cancer.

Using x-ray crystallography as our primary experimental technique, we are attempting to understand the molecular basis for insulin receptor activation and for recruitment of downstream signaling proteins to the activated (phosphorylated) insulin receptor. Several cytoplasmic adapter proteins bind to the activated insulin receptor, including insulin receptor substrate (IRS) proteins and APS, which are positive factors in insulin signaling pathways culminating in glucose uptake. The insulin receptor is downregulated by the adapter proteins Grb10 and Grb14 as well as the tyrosine phosphatase PTP1B. We are determining crystal structures of complexes between these proteins and the insulin receptor kinase domain to elucidate the modes of interaction and the determinants of specificity.

Another project concerns the IGF1 receptor, which is highly related in sequence and structure to the insulin receptor, but has distinct biological functions, one of which is cell survival. Therefore, this RTK is a potential target for inhibition in tumor cells. In collaboration with Dr. Todd Miller at SUNY-Stony Brook, we have determined the three-dimensional structure of the IGF1 receptor kinase domain using x-ray crystallography. Several amino acid differences between the IGF1 receptor and the insulin receptor near the ATP binding cleft might be exploited by small-molecule inhibitors to gain selectivity for the IGF1 receptor over the insulin receptor. To this end, structural studies of inhibitors bound to the IGF1 receptor kinase are being pursued.

Another RTK of interest is MuSK, or muscle-specific kinase, which is expressed exclusively in muscle cells and plays an essential role in the formation of neuromuscular synapses, by promoting clustering of acetylcholine receptors. Activation of MuSK by agrin results in autophosphorylation of several tyrosines in the cytoplasmic domain of MuSK. In a collaboration with Dr. Steven Burden at the NYU School of Medicine, we have determined the crystal structure of the cytoplasmic (tyrosine kinase-containing) domain of MuSK to understand how kinase activity is regulated in this receptor. The structure reveals that MuSK is strongly autoinhibited by the kinase activation loop and suggests that an additional in vivo component might contribute to negative regulation by binding to the juxtamembrane region of MuSK.

Research Interests

Structural Studies of Receptor Tyrosine Kinases

Research Keywords

insulin receptor, protein tyrosine kinases, signal transduction, tyrosine kinase inhibitors, x-ray crystallography

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All data from NYU Health Sciences Library Faculty Bibliography — -

Contact:
http://hsl.med.nyu.edu/faculty-bibliography-search#about

Cytokine signaling exposed
Hubbard, Stevan R
2011 Jan 12;19(1):1-2, Structure
— id: 119236, year: 2011, vol: 19, page: 1, stat: Journal Article,

Structure-guided identification of a laminin binding site on the laminin receptor precursor
Jamieson, Kelly V; Hubbard, Stevan R; Meruelo, Daniel
2011 Jan 7;405(1):24-32, Journal of molecular biology
— id: 116207, year: 2011, vol: 405, page: 24, stat: Journal Article,

The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling
Ungureanu, Daniela; Wu, Jinhua; Pekkala, Tuija; Niranjan, Yashavanthi; Young, Clifford; Jensen, Ole N; Xu, Chong-Feng; Neubert, Thomas A; Skoda, Radek C; Hubbard, Stevan R; Silvennoinen, Olli
2011 ;18(9):971-976, Nature structural & molecular biology
— id: 137017, year: 2011, vol: 18, page: 971, stat: Journal Article,

Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK)
Zhang, Wei; Coldefy, Anne-Sophie; Hubbard, Stevan R; Burden, Steven J
2011 Nov 25;286(47):40624-40630, Journal of biological chemistry
— id: 150244, year: 2011, vol: 286, page: 40624, stat: Journal Article,

The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization
Bergamin, Elisa; Hallock, Peter T; Burden, Steven J; Hubbard, Stevan R
2010 Jul 9;39(1):100-109, Molecular cell
— id: 110694, year: 2010, vol: 39, page: 100, stat: Journal Article,

Molecular analysis of the prokaryotic ubiquitin-like protein (Pup) conjugation pathway in Mycobacterium tuberculosis
Cerda-Maira, Francisca A; Pearce, Michael J; Fuortes, Michele; Bishai, William R; Hubbard, Stevan R; Darwin, K Heran
2010 Sep;77(5):1123-1135, Molecular microbiology
— id: 114585, year: 2010, vol: 77, page: 1123, stat: Journal Article,

Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14
Depetris, Rafael S; Wu, Jinhua; Hubbard, Stevan R
2009 Aug;16(8):833-839, Nature structural & molecular biology
— id: 101332, year: 2009, vol: 16, page: 833, stat: Journal Article,

The juxtamembrane region of EGFR takes center stage
Hubbard, Stevan R
2009 Jun 26;137(7):1181-1183, Cell
— id: 100621, year: 2009, vol: 137, page: 1181, stat: Journal Article,

Crystal structure of the frizzled-like cysteine-rich domain of the receptor tyrosine kinase MuSK
Stiegler, Amy L; Burden, Steven J; Hubbard, Stevan R
2009 Oct 16;393(1):1-9, Journal of molecular biology
— id: 102933, year: 2009, vol: 393, page: 1, stat: Journal Article,

Crystal structure of the human laminin receptor precursor
Jamieson, Kelly V; Wu, Jinhua; Hubbard, Stevan R; Meruelo, Daniel
2008 Feb 8;283(6):3002-3005, Journal of biological chemistry
— id: 76763, year: 2008, vol: 283, page: 3002, stat: Journal Article,

Lrp4 is a receptor for Agrin and forms a complex with MuSK
Kim, Natalie; Stiegler, Amy L; Cameron, Thomas O; Hallock, Peter T; Gomez, Andrea M; Huang, Julie H; Hubbard, Stevan R; Dustin, Michael L; Burden, Steven J
2008 Oct 17;135(2):334-342, Cell
— id: 93378, year: 2008, vol: 135, page: 334, stat: Journal Article,

How IRE1 reacts to ER stress
Ron, David; Hubbard, Stevan R
2008 Jan 11;132(1):24-26, Cell
— id: 76457, year: 2008, vol: 132, page: 24, stat: Journal Article,

Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor
Wu, Jinhua; Li, Wanqing; Craddock, Barbara P; Foreman, Kenneth W; Mulvihill, Mark J; Ji, Qun-sheng; Miller, W Todd; Hubbard, Stevan R
2008 Jul 23;27(14):1985-1994, EMBO journal
— id: 80313, year: 2008, vol: 27, page: 1985, stat: Journal Article,

Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2
Wu, Jinhua; Tseng, Yolanda D; Xu, Chong-Feng; Neubert, Thomas A; White, Morris F; Hubbard, Stevan R
2008 Mar;15(3):251-258, Nature structural & molecular biology
— id: 76468, year: 2008, vol: 15, page: 251, stat: Journal Article,

Receptor tyrosine kinases: mechanisms of activation and signaling
Hubbard, Stevan R; Miller, W Todd
2007 Apr;19(2):117-123, Current opinion in cell biology
— id: 72808, year: 2007, vol: 19, page: 117, stat: Journal Article,

Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3
Bergamin, Elisa; Wu, Jinhua; Hubbard, Stevan R
2006 Aug;14(8):1285-1292, Structure
— id: 68986, year: 2006, vol: 14, page: 1285, stat: Journal Article,

Structural Basis for Phosphotyrosine Recognition by the Src Homology-2 Domains of the Adapter Proteins SH2-B and APS
Hu, Junjie; Hubbard, Stevan R
2006 Aug 4;361(1):69-79, Journal of molecular biology
— id: 65226, year: 2006, vol: 361, page: 69, stat: Journal Article,

EGF receptor activation: push comes to shove
Hubbard, Stevan R
2006 Jun 16;125(6):1029-1031, Cell
— id: 65227, year: 2006, vol: 125, page: 1029, stat: Journal Article,

Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK
Stiegler, Amy L; Burden, Steven J; Hubbard, Stevan R
2006 Dec 1;364(3):424-433, Journal of molecular biology
— id: 70021, year: 2006, vol: 364, page: 424, stat: Journal Article,

Structural basis for inhibition of the insulin receptor by the adaptor protein grb14
Depetris, Rafael S; Hu, Junjie; Gimpelevich, Ilana; Holt, Lowenna J; Daly, Roger J; Hubbard, Stevan R
2005 Oct 28;20(2):325-333, Molecular cell
— id: 58752, year: 2005, vol: 20, page: 325, stat: Journal Article,

Bisubstrate analog probes for the insulin receptor protein tyrosine kinase: molecular yardsticks for analyzing catalytic mechanism and inhibitor design
Hines, Aliya C; Parang, Keykavous; Kohanski, Ronald A; Hubbard, Stevan R; Cole, Philip A
2005 Aug;33(4):285-297, Bioorganic chemistry
— id: 65228, year: 2005, vol: 33, page: 285, stat: Journal Article,

Structural Characterization of a Novel Cbl Phosphotyrosine Recognition Motif in the APS Family of Adapter Proteins
Hu, Junjie; Hubbard, Stevan R
2005 May 13;280(19):18943-18949, Journal of biological chemistry
— id: 52545, year: 2005, vol: 280, page: 18943, stat: Journal Article,

EGF receptor inhibition: attacks on multiple fronts
Hubbard, Stevan R
2005 Apr;7(4):287-288, Cancer cell
— id: 52544, year: 2005, vol: 7, page: 287, stat: Journal Article,

Crystal structure of a complex between protein tyrosine phosphatase 1B and the insulin receptor tyrosine kinase
Li, Shiqing; Depetris, Rafael S; Barford, David; Chernoff, Jonathan; Hubbard, Stevan R
2005 Nov;13(11):1643-1651, Structure
— id: 62350, year: 2005, vol: 13, page: 1643, stat: Journal Article,

Juxtamembrane autoinhibition in receptor tyrosine kinases
Hubbard, Stevan R
2004 Jun;5(6):464-471, Nature reviews. Molecular cell biology
— id: 43031, year: 2004, vol: 5, page: 464, stat: Journal Article,

Oncogenic mutations in B-Raf: some losses yield gains
Hubbard, Stevan R
2004 Mar 19;116(6):764-766, Cell
— id: 43032, year: 2004, vol: 116, page: 764, stat: Journal Article,

Agrin/MuSK signaling: willing and Abl
Burden, Steven J; Fuhrer, Christian; Hubbard, Stevan R
2003 Jul;6(7):653-654, Nature neuroscience
— id: 65229, year: 2003, vol: 6, page: 653, stat: Journal Article,

Structural Basis for Recruitment of the Adaptor Protein APS to the Activated Insulin Receptor
Hu, Junjie; Liu, Jun; Ghirlando, Rodolfo; Saltiel, Alan R; Hubbard, Stevan R
2003 Dec;12(6):1379-1389, Molecular cell
— id: 40090, year: 2003, vol: 12, page: 1379, stat: Journal Article,

Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor
Li, Shiqing; Covino, Nicole D; Stein, Evan G; Till, Jeffrey H; Hubbard, Stevan R
2003 Jul 11;278(28):26007-26014, Journal of biological chemistry
— id: 39243, year: 2003, vol: 278, page: 26007, stat: Journal Article,

Structural Basis for Dimerization of the Grb10 Src Homology 2 Domain. IMPLICATIONS FOR LIGAND SPECIFICITY
Stein, Evan G; Ghirlando, Rodolfo; Hubbard, Stevan R
2003 Apr 11;278(15):13257-13264, Journal of biological chemistry
— id: 34133, year: 2003, vol: 278, page: 13257, stat: Journal Article,

Protein tyrosine kinases: autoregulation and small-molecule inhibition
Hubbard, Stevan R
2002 Dec;12(6):735-741, Current opinion in structural biology
— id: 39343, year: 2002, vol: 12, page: 735, stat: Journal Article,

Crystal Structure of the MuSK Tyrosine Kinase. Insights into Receptor Autoregulation
Till, Jeffrey H; Becerra, Manuel; Watty, Anke; Lu, Yun; Ma, Yuliang; Neubert, Thomas A; Burden, Steven J; Hubbard, Stevan R
2002 Sep;10(9):1187-1187, Structure
— id: 32906, year: 2002, vol: 10, page: 1187, stat: Journal Article,

Structure and autoregulation of the insulin-like growth factor 1 receptor kinase
Favelyukis S; Till JH; Hubbard SR; Miller WT
2001 Dec;8(12):1058-1063, Nature structural biology
— id: 24974, year: 2001, vol: 8, page: 1058, stat: Journal Article,

Theme and variations: juxtamembrane regulation of receptor protein kinases
Hubbard SR
2001 Sep;8(3):481-482, Molecular cell
— id: 24975, year: 2001, vol: 8, page: 481, stat: Journal Article,

Mechanism-based design of a protein kinase inhibitor
Parang K; Till JH; Ablooglu AJ; Kohanski RA; Hubbard SR; Cole PA
2001 Jan;8(1):37-41, Nature structural biology
— id: 20816, year: 2001, vol: 8, page: 37, stat: Journal Article,

The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors
Stein EG; Gustafson TA; Hubbard SR
2001 Mar 30;493(2-3):106-111, FEBS letters
— id: 20817, year: 2001, vol: 493, page: 106, stat: Journal Article,

Crystallographic and solution studies of an activation loop mutant of the insulin receptor tyrosine kinase: insights into kinase mechanism
Till JH; Ablooglu AJ; Frankel M; Bishop SM; Kohanski RA; Hubbard SR
2001 Mar 30;276(13):10049-10055, Journal of biological chemistry
— id: 20815, year: 2001, vol: 276, page: 10049, stat: Journal Article,

Probing the catalytic mechanism of the insulin receptor kinase with a tetrafluorotyrosine-containing peptide substrate
Ablooglu, A J; Till, J H; Kim, K; Parang, K; Cole, P A; Hubbard, S R; Kohanski, R A
2000 Sep;275(39):30394-30398, Journal of biological chemistry
— id: 163497, year: 2000, vol: 275, page: 30394, stat: Journal Article,

PROTEIN TYROSINE KINASE STRUCTURE AND FUNCTION
Hubbard SR; Till JH
2000 ;69:373-398, Annual review of biochemistry
— id: 11520, year: 2000, vol: 69, page: 373, stat: Journal Article,

SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors
Laird AD; Vajkoczy P; Shawver LK; Thurnher A; Liang C; Mohammadi M; Schlessinger J; Ullrich A; Hubbard SR; Blake RA; Fong TA; Strawn LM; Sun L; Tang C; Hawtin R; Tang F; Shenoy N; Hirth KP; McMahon G; Cherrington
2000 Aug 1;60(15):4152-4160, Cancer research
— id: 20814, year: 2000, vol: 60, page: 4152, stat: Journal Article,

Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity
Plotnikov AN; Hubbard SR; Schlessinger J; Mohammadi M
2000 May 12;101(4):413-424, Cell
— id: 11676, year: 2000, vol: 101, page: 413, stat: Journal Article,

Structural analysis of receptor tyrosine kinases
Hubbard SR
1999 ;71(3-4):343-358, Progress in biophysics & molecular biology
— id: 6129, year: 1999, vol: 71, page: 343, stat: Journal Article,

Crystal structure of the ARF-GAP domain and ankyrin repeats of PYK2-associated protein beta
Mandiyan V; Andreev J; Schlessinger J; Hubbard SR
1999 Dec 15;18(24):6890-6898, EMBO journal
— id: 8587, year: 1999, vol: 18, page: 6890, stat: Journal Article,

Structural basis for FGF receptor dimerization and activation
Plotnikov AN; Schlessinger J; Hubbard SR; Mohammadi M
1999 Sep 3;98(5):641-650, Cell
— id: 8352, year: 1999, vol: 98, page: 641, stat: Journal Article,

Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain
Mohammadi, M; Froum, S; Hamby, J M; Schroeder, M C; Panek, R L; Lu, G H; Eliseenkova, A V; Green, D; Schlessinger, J; Hubbard, S R
1998 Oct;17(20):5896-5904, EMBO journal
— id: 156649, year: 1998, vol: 17, page: 5896, stat: Journal Article,

Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog
Hubbard SR
1997 Sep 15;16(18):5572-5581, EMBO journal
— id: 8449, year: 1997, vol: 16, page: 5572, stat: Journal Article,

Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors
Mohammadi M; McMahon G; Sun L; Tang C; Hirth P; Yeh BK; Hubbard SR; Schlessinger J
1997 May 9;276(5314):955-960, Science
— id: 8448, year: 1997, vol: 276, page: 955, stat: Journal Article,

Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism
Mohammadi M; Schlessinger J; Hubbard SR
1996 Aug 23;86(4):577-587, Cell
— id: 7021, year: 1996, vol: 86, page: 577, stat: Journal Article,

CATALYTIC SPECIFICITY OF PROTEIN-TYROSINE KINASES IS CRITICAL FOR SELECTIVE SIGNALING
SONGYANG, Z; CARRAWAY, KL; ECK, MJ; HARRISON, SC; FELDMAN, RA; MOHAMMADI, M; SCHLESSINGER, J; HUBBARD, SR; SMITH, DP; ENG, C; LORENZO, MJ; PONDER, BAJ; MAYER, BJ; CANTLEY, LC
1995 FEB 9 ;373(6514):536-539, Nature
— id: 87442, year: 1995, vol: 373, page: 536, stat: Journal Article,