Leonidas C. Platanias

Mitogen-activated protein (Map) kinases are widely expressed serine-threonine kinases that mediate important regulatory signals in the cell. Three major groups of Map kinases exist: the p38 Map kinase family, the extracellular signal-regulated kinase (Erk) family, and the c-Jun NH2-terminal kinase (JNK) family. The members of the different Map kinase groups participate in the generation of various cellular responses, including gene transcription, induction of cell death or maintenance of cell survival, malignant transformation, and regulation of cell-cycle progression. Depending on the specific family isoform involved and the cellular context, Map kinase pathways can mediate signals that either promote or suppress the growth of malignant hematopoietic cells. Over the last few years, extensive work by several groups has established that Map kinase pathways play critical roles in the pathogenesis of various hematologic malignancies, providing new molecular targets for future therapeutic approaches. In this review, the involvement of various Map kinase pathways in the pathophysiology of hematologic malignances is summarized and the clinical implications of the recent advances in the field are discussed.

// Young Kwang Chae 1,2,3 , Ayush Arya 3 , Mary-Kate Malecek 3 , Daniel Sanghoon Shin 4 , Benedito Carneiro 1,2,3 , Sunandana Chandra 1,2,3 , Jason Kaplan 1,2,3 , Aparna Kalyan 1,2,3 , Jessica K. Altman 1,2,3 , Leonidas Platanias 1,2,3,5 and Francis Giles 1,2,3 1 Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA 4 David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA 5 Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA Correspondence to: Young Kwang Chae, email: // Keywords : metformin, clinical trials, cancer Received : September 20, 2015 Accepted : March 06, 2016 Published : March 19, 2016 Abstract In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.

SHP-1 is an SH2-containing cytoplasmic tyrosine phosphatase that is widely distributed in cells of the hematopoietic system. SHP-1 plays an important role in the signal transduction of many cytokine receptors, including the receptor for erythropoietin, by associating via its SH2 domains to the receptors and dephosphorylating key substrates. Recent studies have suggested that SHP-1 regulates the function of Jak family tyrosine kinases, as shown by its constitutive association with the Tyk2 kinase and the hyperphosphorylation of Jak kinases in the motheaten cells that lack functional SHP-1. We have examined the interactions of SHP-1 with two tyrosine kinases activated during engagement of the erythropoietin receptor, the Janus family kinase Jak-2 and the c-fps/fes kinase. Immunoblotting studies with extracts from mouse hematopoietic cells demonstrated that Jak2, but not c-fes, was present in anti-SHP-1 immunoprecipitates, suggesting that SHP-1 selectively associates with Jak2 in vivo. Consistent with this, when SHP-1 was coexpressed with these kinases in Cos-7 cells, it associated with and dephosphorylated Jak2 but not c-fes. Transient cotransfection of truncated forms of SHP-1 with Jak2 demonstrated that the SHP-1-Jak2 interaction is direct and is mediated by a novel binding activity present in the N terminus of SHP-1, independently of SH2 domain-phosphotyrosine interaction. Such SHP-1-Jak2 interaction resulted in induction of the enzymatic activity of the phosphatase in in vitro protein tyrosine phosphatase assays. Interestingly, association of the SH2n domain of SHP-1 with the tyrosine phosphorylated erythropoietin receptor modestly potentiated but was not essential for SHP-1-mediated dephosphorylation of Jak2 and had no effect on c-fes phosphorylation. These data indicate that the main mechanism for regulation of Jak2 phosphorylation by SHP-1 involves a direct, SH2-independent interaction with Jak2 and suggest the existence of similar mechanisms for other members of the Jak family of kinases. They also suggest that such interactions may provide one of the mechanisms that control SHP-1 substrate specificity.