The National Institute of Diabetes & Digestive & Kidney Diseases

There are two principal areas of reasearch in my laboratory. The first effort concentrates on the signaling properties of G protein beta-5 complex with regulator of G protein signaling (RGS) proteins. G protein beta-5 is a neuronally-expressed, structurally divergent G protein beta isoform which appears to be functionally specialized. In general, activation of heterotrimeric G proteins by seven-transmembrane spanning receptors results in dissociation of the alpha subunit (in GTP-bound form) from the beta-gamma complex. Both subunits can regulate the function of a variety of downstream effector molecules. RGS proteins act as GTPase activating proteins targeting Galpha subunits and thus can help turn off G protein signalling; recent evidence suggests however that certain RGS proteins can also function as signal transducers or effectors in their own right. The recent observation that G beta-5 forms a tight complex with RGS proteins of the R7 subclass in brain is unexplained by current models of G protein signalling. We are seeking to understand the function of the highly conserved G beta-5/ R7 RGS protein heterodimers in brain.

The other main focus of research in my laboratory aims to understand the pathogenesis and clinical spectrum of familial isolated hyperparathyroidism (FIHP), parathyroid cancer, and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). HPT-JT is a familial syndrome of HPT with autosomal dominant transmission and high but incomplete penetrance. Some 15% of all affected by HPT-JT have parathyroid cancer, and nearly 10% of adult cases appear to be silent carriers. The trait links to the HRPT2 locus at 1q25-q31, a gene that was recently identified by the Metabolic Diseases Branch working with investigators in the NHGRI in the context of an international consortium. HRPT2 is a widely expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which the name parafibromin was proposed. Parafibromin bears some homology to cdc73, a yeast protein component of the Paf1 transcriptional regulatory complex. HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of many sporadic parathyroid tumors. Recent clinical studies in our Branch demonstrated that germline HRPT2 mutation is a rare cause of FIHP. Current studies are focused on the expression and function of the HRPT2 gene product parafibromin.

Marx SJ, Simonds WF Hereditary hormone excess: genes, molecular pathways, and syndromes. Endocr Rev (26): 615-61, 2005. [Full Text/Abstract]

Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ, Simonds WF Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene (24): 1272-6, 2005. [Full Text/Abstract]

Simonds WF, Woodard GE, Zhang JH Assays of nuclear localization of R7/Gbeta5 complexes. Methods Enzymol (390): 210-23, 2004. [Full Text/Abstract]

Simonds WF Robbins CM Agarwal SK Hendy GN Carpten JD Marx SJ Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab (89): 96-102, 2004. [Full Text/Abstract]

Simonds WF G protein-regulated signaling dysfunction in human disease. J Investig Med (51): 194-214, 2003. [Full Text/Abstract]

Rojkova AM Woodard GE Huang TC Combs CA Zhang JH Simonds WF Ggamma subunit-selective G protein beta 5 mutant defines regulators of G protein signaling protein binding requirement for nuclear localization. J Biol Chem (278): 12507-12, 2003. [Full Text/Abstract]

Weinstein LS Simonds WF HRPT2, a marker of parathyroid cancer. N Engl J Med (349): 1691-2, 2003. [Full Text/Abstract]

Simonds WF James-Newton LA Agarwal SK Yang B Skarulis MC Hendy GN Marx SJ Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) (81): 1-26, 2002. [Full Text/Abstract]

Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Hoog A, Heath H 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, et al HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genetics(32): 676-80, 2002.

Zhang JH Barr VA Mo Y Rojkova AM Liu S Simonds WF Nuclear localization of G protein beta 5 and regulator of G protein signaling 7 in neurons and brain. J Biol Chem (276): 10284-9, 2001. [Full Text/Abstract]

Skiba NP Martemyanov KA Elfenbein A Hopp JA Bohm A Simonds WF Arshavsky VY RGS9-G beta 5 substrate selectivity in photoreceptors. Opposing effects of constituent domains yield high affinity of RGS interaction with the G protein-effector complex. J Biol Chem (276): 37365-72, 2001. [Full Text/Abstract]

Zhang JH Simonds WF Copurification of brain G-protein beta5 with RGS6 and RGS7. J Neurosci (20): RC59, 2000. [Full Text/Abstract]