Education:
MD 1996 Medicine - University of Rome "Tor Vergata" Rome, Italy
Postdoctoral Research Fellowship:
2000-2005 The Burnham Institute, La Jolla, California
Started at USC: 2005
Research Topics: Signal Transduction, Immunology, Human/Mammalian Genetics, Diabetes/Metabolic Diseases
Research Description
Tyrosine phosphorylation of cellular proteins is a key mechanism for signal transduction and is the result of the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Our main research focus is in the role of PTPs in human T cell-mediated diseases. Two PTPs are presently under investigation in our laboratory, 1) the lymphoid tyrosine phosphatase and 2) the low molecular weight tyrosine phosphatase
1) The lymphoid tyrosine phosphatase (LYP), encoded by the gene PTPN22 is a PTP with expression restricted to hemopoietic cells. In T cells LYP acts as a gatekeeper of T lymphocyte activation, and negatively modulates the activity of Src family kinases and ZAP-70. The molecular mechanism by which LYP tempers T lymphocyte activation involves the formation of a complex between LYP and the protein tyrosine kinase Csk. A recently described functional polymorphism (SNP) in the PTPN22 gene, which abolishes binding of LYP to Csk, predisposes humans to T1D, rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune diseases. Current projects in the laboratory are aimed at clarifying the role of LYP in T cell physiology and the mechanism of action of LYP genetic polymorphism in human autoimmunity.
2) The low molecular weight protein tyrosine phosphatase (LMPTP, LMW-PTP, cLMWPTP), encoded by the gene ACP1 is an ubiquitous PTP involved in modulation of signaling through several human receptor. In T cells LMPTP plays a positive role in TCR signaling by dephosphorylating the Tyr-292 residue of ZAP-70. Current projects in the laboratory are aimed at isolating the physiological substrate(s) of LMPTP in T cells, and at analyzing the possible role of LMPTP in rheumatoid arthritis and other human autoimmune diseases.
Selected Publications
Saccucci P, Del Duca E, Rapini N, Verrotti A, Piccinini S, Maccari A, Canu G, Angelini F, Fontana L, Giannini C, Chiarelli F, Manca Bitti ML, Bottini N. - Association between PTPN22 C1858T and type 1 diabetes: a replication in continental Italy. - Tissue Antigens [ 2008 ] Jan 7; . PubMed
Zoledziewska M, Perra C, Orr?? V, Moi L, Frongia P, Congia M, Bottini N, Cucca F. - Further evidence of a primary, causal association of the PTPN22 620W variant with type 1 diabetes. - Diabetes [ 2008 ] Jan;57(1):229-34 . PubMed
Vang T, Miletic AV, Bottini N, Mustelin T. - Protein tyrosine phosphatase PTPN22 in human autoimmunity. - Autoimmunity [ 2007 ] Sep;40(6):453-61 . PubMed
Bottini N, Vang T, Cucca F, Mustelin T. - Role of PTPN22 in type 1 diabetes and other autoimmune diseases. - Semin Immunol [ 2006 ] Aug;18(4):207-13 . PubMed
Nika K, Charvet C, Williams S, Tautz L, Bruckner S, Rahmouni S, Bottini N, Schoenberger SP, Baier G, Altman A, Mustelin T. - Lipid raft targeting of hematopoietic protein tyrosine phosphatase by protein kinase C theta-mediated phosphorylation. - Mol Cell Biol [ 2006 ] Mar;26(5):1806-16 . PubMed
Mijakovic I, Petranovic D, Bottini N, Deutscher J, Ruhdal Jensen P. - Protein-tyrosine phosphorylation in Bacillus subtilis. - J Mol Microbiol Biotechnol [ 2005 ] 9(3-4):189-97 . PubMed
Wang Y, Vachon E, Zhang J, Cherepanov V, Kruger J, Li J, Saito K, Shannon P, Bottini N, Huynh H, Ni H, Yang H, McKerlie C, Quaggin S, Zhao ZJ, Marsden PA, Mustelin T, Siminovitch KA, Downey GP. - Tyrosine phosphatase MEG2 modulates murine development and platelet and lymphocyte activation through secretory vesicle function. - J Exp Med [ 2005 ] Dec 5;202(11):1587-97 . PubMed
Vang T, Congia M, Macis MD, Musumeci L, Orr?? V, Zavattari P, Nika K, Tautz L, Tasken K, Cucca F, Mustelin T, Bottini N. - Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. - Nat Genet [ 2005 ] Dec;37(12):1317-9 . PubMed
Wu H, Cantor RM, Graham DS, Lingren CM, Farwell L, Jager PL, Bottini N, Grossman JM, Wallace DJ, Hahn BH, Julkunen H, Hebert LA, Rovin BH, Birmingham DJ, Rioux JD, Yu CY, Kere J, Vyse TJ, Tsao BP. - Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease. - Arthritis Rheum [ 2005 ] Aug;52(8):2396-402 . PubMed
Musumeci L, Bongiorni C, Tautz L, Edwards RA, Osterman A, Perego M, Mustelin T, Bottini N. - Low-molecular-weight protein tyrosine phosphatases of Bacillus subtilis. - J Bacteriol [ 2005 ] Jul;187(14):4945-56 . PubMed
