Joseph Schlessinger, PhD
Biography
Research & Publications
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Research Summary
Our laboratory is exploring the mode of action of growth factor receptors and the intracellular signaling pathways that are activated in response to growth factor stimulation. Receptor tyrosine kinases and cytoplasmic protein tyrosine kinases play a critical role in the control of many cellular processes including: cell proliferation, differentiation, metabolism, as well as cell survival and cell migration. Various diseases are caused by dysfunctions in receptor tyrosine kinases or in critical components of signaling pathways that are activated by receptors tyrosine kinases. In addition, various developmental disorders are caused by loss of function mutations in receptor tyrosine kinases. We are using biochemical and genetic approaches as well as X-ray crystallography to determine the mechanism of activation of receptor tyrosine kinases, how they recruit target proteins, and the mode of action of downstream signaling proteins in normal cellular processes and in diseases caused by dysfunctional receptor tyrosine kinases.
Specialized Terms: Growth factor receptors; Intracellular signaling pathways; Protein kinases; Phosphorylation; SH2, SH3 and other protein modules involved in signal transduction; Drug discovery
Extensive Research Description
Research Interests
Pharmacology; Phosphorylation; Protein Kinases; Signal Transduction; Crystallography, X-Ray; Receptor Protein-Tyrosine Kinases; Cell Proliferation; Drug Discovery
Selected Publications
- Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domainKobashigawa Y, Amano S, Yokogawa M, Kumeta H, Morioka H, Inouye M, Schlessinger J, Inagaki F. Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain Genes To Cells 2015, 20: 860-870. PMID: 26300540, DOI: 10.1111/gtc.12277.
- Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomasKrauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, McCusker JP, Ma S, Cheng E, Straub R, Serin M, Bosenberg M, Ariyan S, Narayan D, Sznol M, Kluger HM, Mane S, Schlessinger J, Lifton RP, Halaban R. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas Nature Genetics 2015, 47: 996-1002. PMID: 26214590, PMCID: PMC4916843, DOI: 10.1038/ng.3361.
- FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axisPerry RJ, Lee S, Ma L, Zhang D, Schlessinger J, Shulman GI. FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis Nature Communications 2015, 6: 6980. PMID: 25916467, PMCID: PMC4413509, DOI: 10.1038/ncomms7980.
- Heparin is an activating ligand of the orphan receptor tyrosine kinase ALKMurray PB, Lax I, Reshetnyak A, Ligon GF, Lillquist JS, Natoli EJ, Shi X, Folta-Stogniew E, Gunel M, Alvarado D, Schlessinger J. Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK Science Signaling 2015, 8: ra6. PMID: 25605972, DOI: 10.1126/scisignal.2005916.
- Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical CarcinomaJuhlin CC, Goh G, Healy JM, Fonseca AL, Scholl UI, Stenman A, Kunstman JW, Brown TC, Overton JD, Mane SM, Nelson-Williams C, Bäckdahl M, Suttorp AC, Haase M, Choi M, Schlessinger J, Rimm DL, Höög A, Prasad ML, Korah R, Larsson C, Lifton RP, Carling T. Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma The Journal Of Clinical Endocrinology & Metabolism 2014, 100: e493-e502. PMID: 25490274, PMCID: PMC5393505, DOI: 10.1210/jc.2014-3282.
- The docking protein FRS2α is a critical regulator of VEGF receptors signalingChen PY, Qin L, Zhuang ZW, Tellides G, Lax I, Schlessinger J, Simons M. The docking protein FRS2α is a critical regulator of VEGF receptors signaling Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 5514-5519. PMID: 24706887, PMCID: PMC3992672, DOI: 10.1073/pnas.1404545111.
- Receptor Tyrosine Kinases: Legacy of the First Two DecadesSchlessinger J. Receptor Tyrosine Kinases: Legacy of the First Two Decades Cold Spring Harbor Perspectives In Biology 2014, 6: a008912. PMID: 24591517, PMCID: PMC3949355, DOI: 10.1101/cshperspect.a008912.
- Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimersOpatowsky Y, Lax I, Tomé F, Bleichert F, Unger VM, Schlessinger J. Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 1772-1777. PMID: 24449920, PMCID: PMC3918759, DOI: 10.1073/pnas.1323254111.
- Differential TAM receptor–ligand–phospholipid interactions delimit differential TAM bioactivitiesLew ED, Oh J, Burrola PG, Lax I, Zagórska A, Través PG, Schlessinger J, Lemke G. Differential TAM receptor–ligand–phospholipid interactions delimit differential TAM bioactivities ELife 2014, 3: e03385. PMID: 25265470, PMCID: PMC4206827, DOI: 10.7554/elife.03385.
- Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal regionReshetnyak AV, Nelson B, Shi X, Boggon TJ, Pavlenco A, Mandel-Bausch EM, Tome F, Suzuki Y, Sidhu SS, Lax I, Schlessinger J. Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 17832-17837. PMID: 24127596, PMCID: PMC3816449, DOI: 10.1073/pnas.1317118110.
- Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinomaZhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, Guzzo F, English DP, Varughese J, Gasparrini S, Bortolomai I, Buza N, Hui P, Abu-Khalaf M, Ravaggi A, Bignotti E, Bandiera E, Romani C, Todeschini P, Tassi R, Zanotti L, Carrara L, Pecorelli S, Silasi DA, Ratner E, Azodi M, Schwartz PE, Rutherford TJ, Stiegler AL, Mane S, Boggon TJ, Schlessinger J, Lifton RP, Santin AD. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 2916-2921. PMID: 23359684, PMCID: PMC3581983, DOI: 10.1073/pnas.1222577110.
- RAC1P29S is a spontaneously activating cancer-associated GTPaseDavis MJ, Ha BH, Holman EC, Halaban R, Schlessinger J, Boggon TJ. RAC1P29S is a spontaneously activating cancer-associated GTPase Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 912-917. PMID: 23284172, PMCID: PMC3549122, DOI: 10.1073/pnas.1220895110.
- Cell Signaling by Receptor Tyrosine KinasesLemmon MA, Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases Cell 2010, 141: 1117-1134. PMID: 20602996, PMCID: PMC2914105, DOI: 10.1016/j.cell.2010.06.011.
- Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cellsBae JH, Boggon TJ, Tomé F, Mandiyan V, Lax I, Schlessinger J. Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 2866-2871. PMID: 20133753, PMCID: PMC2840318, DOI: 10.1073/pnas.0914157107.
- The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding SiteBae JH, Lew ED, Yuzawa S, Tomé F, Lax I, Schlessinger J. The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site Cell 2009, 138: 514-524. PMID: 19665973, PMCID: PMC4764080, DOI: 10.1016/j.cell.2009.05.028.
- Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activationLew ED, Bae JH, Rohmann E, Wollnik B, Schlessinger J. Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activation Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 19802-19807. PMID: 18056630, PMCID: PMC2148379, DOI: 10.1073/pnas.0709905104.
- Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell FactorYuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J. Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor Cell 2007, 130: 323-334. PMID: 17662946, DOI: 10.1016/j.cell.2007.05.055.