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Principles of Cell Signaling and Biological Consequences

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Final Forum: Student #1

10 May 2005

student number 01

Papers:
1. The C2 domain of PKCdelta is a Phosphotyrosine Binding Domain, Cell, Vol. 121, 271-280 April 22, 2005.[PubMed] [Online Journal]
2. Phosphorylation and Functional inactivation of TSC2 by ERK: Implications for Tuberous Sclerosis and Cancer Pathogenesis, Cell, Vol. 121, 179-193 April 22, 2005. [PubMed] [Online Journal]

Paper 1: Cellular signal transduction depends are protein-protein interactions that are regulated by post-translational modifications like phosphorylation, sumolation, acetylation, ubiquitination to name a few. Phosphorylation in particular is very well studied in the last decade, especially protein domains that recognize phosphorylated residues. There appears to be two distinct kinase groups that are responsible for cellular phosphorylation reactions, Serine/Theronine kinases and Tyrosine kinases. And associated with the respective phosphorylated residues are their phosphorylation binding domains. For example, SH2 (src homology 2 domain) and PTB (phosphotyrosine binding domain) are well know for their affinity to phosphotyrosine residues; whereas, FHA (forkhead associated domains) and 14-3-3 proteins binds to phosphoserine and phosphotheronine. However, until this paper, there is no evidence that phosphoserine/threonine kinases can bind to phosphotyrosine peptides or vice versa. This paper provides the first evidence that such interaction exist in nature. PKCdelta, a Ser/Thr kinase, contains a C2 domain that binds to phosphotyrosine peptides. Previous research have shown that PKCdelta interacts with Src (a tyrosine kinase), which led the authors to surmise that there may be an intermediate protein that mediate this interaction. Indeed, they found that CDCP1, a transmembrane protein, is a Src substrate and mediates the interaction between Src and PKCdelta. The scheme proposed is that Src phosphorylates CDCP1 on a tyrosine residue, which is the docking site for PKCdelta binding via its C2 domain. This is confirmed via biochemical and structural studies that include x-ray crystallography of the association between C2 domain and phosphotyrosine peptides. This paper reveals a new mode of interaction between signal molecules that potentially have very significant consequences on cellular signaling networks. One can surmise that there maybe a phosphotyrosin kinase that can bind to phosphorserine/theronine residues waiting to be characterized.

Paper 2: Tuberous sclerosis (TSC), an autosomal dominant tumor syndrome, is a result of mutations in TSC1 and TSC2 genes. It has been established earlier that AKT is upstream of TSC1-2 complex and phosphorylate TSC1-2 complex to inactive form. TSC1 and 2 heterodimeric complex suppresses mammalian target of rapamycin (MTOR). Previous research has shown that TSC2 is a Rheb (ras homolog enriched in brain)-GAP where it activates Rheb -GTP hydolysis to Rheb-GDP. Rheb in its GTP-bound form activates mTOR, which leads to activation of p70s6k and eIF4E resulting in increased translation. Thus, a distinct PI3K/AKT path of regulation is well characterized. This paper demonstrates that in addition to this PI3K/AKT regulatory pathway, TSC2 is further regulated by MAPK pathway via Erk1/2. MAPK and PI3K/AKT pathways are two major pathways that are disrupted in human cancer. Finding a common regulated molecule like TSC2 in their respective cascade explains the clinical observation that in TSC2 normal tumors there is a correlative increase in Erk1/2 activity. The experiments in this paper have demonstrated that TSC2 is phosphorylated by Erk2 on S664 residue due to MAPK pathway activation. This phosphorylation leads to TSC1-2 complex dissociation and reduced activity of TSC2 towards repressing proliferation. The mouse studies conclusively demonstrated that Erk phosphorylation on S664 leads to reduced TSC2 tumor suppressive activity. Thus, this signaling convergence leads to a biological and clinical relevant outcome.

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882