***** seminarMLから情報転載 *****

Date and Time:January 31&s_comma; 2011&s_comma; Monday 17:00 - 18:30

Venue : Second Building&s_comma; 2nd floor Large lecture room

Speaker:Prof. Benjamin G. Neel&s_comma; Director

Ontario Cancer Institute and Campbell Family Research Institute&s_comma; Toronto&s_comma; Canada

Seminar Title:Signal Transduction in Health and Disease

(Language) English

Summary:The RAS/MAPK pathway plays a critical role in regulating cell proliferation&s_comma; growth&s_comma; differentiatoon and survival&s_comma; and is frequently dysregulated in neoplastic disorders. In addition&s_comma; work over the past ten years has identified mutations in different RAS/MAPK family members in several developmental disorders&s_comma; which are now collectively termed “RASopathies.” Although these genetic diseases share many features&s_comma; they also have important phenotypic differences. Thus&s_comma; a detailed understanding of the pathogenesis of RASopathies may shed important light on the nuances of RAS/MAPK pathway regulation. Noonan syndrome (NS) is a fairly common&s_comma; autosomal dominant genetic syndrome with pleiotropic features including cardiac abnormalities (valvuloseptal defects&s_comma; hypertrophic cardiomyopathy)&s_comma; short stature and facial dysmorphia&s_comma; among others. Germline gain-of-function mutations in PTPN11 (which encodes SHP2) are the most common cause of NS; other disease alleles include SOS1&s_comma; KRAS&s_comma; NRAS&s_comma; SHOC2 and RAF1. Remarkably&s_comma; some NS-associated RAF1 mutants show increased in vitro kinase activity&s_comma; whereas others are associated with either normal or reduced kinase activity. Unlike PTPN11-mutant-associated NS&s_comma; in which hypertrophic cardiomyopathy (HCM) is rare&s_comma; human NS caused by RAF1 mutants with increased kinase activity (but not with the other type of RAF1 mutants) shows a strong correlation with HCM. To better understand how RAF1 mutants differentially lead to NS phenotypes&s_comma; we generated mouse models for increased (L613V) and decreased (D486N) RAF1 activity. Our results show that mice L613V/+ mice exhibit LV hypertrophy and dilatation&s_comma; as well as other NS features&s_comma; whereas D486N/+ mice display gender-dependent NS phenotypes but not HCM. D486N homozygotes display increased cardiac wall thickness but do not dilate&s_comma; and these mice also have variable differences in stature. Biochemical analyses show that both types of Raf1 allele cause increased activation of the Ras/Erk pathway. Remarkably&s_comma; all NS features in L613V/+ mice may be ameliorated by appropriately timed post-natal Mek-inhibitor treatment. These models reveal novel kinase independent features of Raf1&s_comma; and provide a conceptual basis for the distinct and shared pathological features of these disorders. Our data also suggest new therapeutic options for NS patients.

Recent work has also focused attention on an entirely different mode of regulation of the RAS/MAPK pathway and other signal transduction cascades&s_comma; via the use of reactive oxygen species (ROS) as second messengers. By virtue of their extremely reactive cysteinyl residue&s_comma; PTPs are believed to be major ROS targets. I also will discuss a new global proteomic method to detect PTP oxidation&s_comma; which can also be used for profiling PTPs in mammalian cells and tissues. This method reveals dramatic and specific differences in PTP oxidation in different types of human cancer cell lines; thus&s_comma; differential PTP oxidation might represent a new layer of complexity in oncogenic transformation.

Host: Noriko Gotoh (Division of Systems Biomedical Technology )&s_comma;

Yuji Yamanashi (Division of Genetics)