Erica A Golemis

Publications of Erica A Golemis

• Interaction trap/two-hybrid system to identify interacting proteins.

  Authors: Erica A Golemis, Ilya Serebriiskii, Russell L Finley, Mikhail G Kolonin, Jeno Gyuris, Roger Brent

  Current protocols in cell biology / editorial board, Juan S. Bonifacino ... [et al.]. 12/2011; Chapter 17:Unit 17.3..

  The yeast two-hybrid method (or interaction trap) is a powerful technique for detecting protein interactions. The procedure is performed using transcriptional activation of a dual reporter system inThe yeast two-hybrid method (or interaction trap) is a powerful technique for detecting protein interactions. The procedure is performed using transcriptional activation of a dual reporter system in yeast to identify interactions between a protein of interest (the bait protein) and the candidate proteins for interaction. The method can be used to screen a protein library for interactions with a bait protein or to test for association between proteins that are expected to interact based on prior evidence. Interaction mating facilitates the screening of a library with multiple bait proteins.

• Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer.

  Authors: Ranee Mehra, Ilya G Serebriiskii, Roland L Dunbrack, Matthew K Robinson, Barbara Burtness, Erica A Golemis

  Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 09/2011; 14(6):260-79.

  Agents targeting EGFR and related ErbB family proteins are valuable therapies for the treatment of many cancers. For some tumor types, including squamous cell carcinomas of the head and neck (SCCHN),Agents targeting EGFR and related ErbB family proteins are valuable therapies for the treatment of many cancers. For some tumor types, including squamous cell carcinomas of the head and neck (SCCHN), antibodies targeting EGFR were the first protein-directed agents to show clinical benefit, and remain a standard component of clinical strategies for management of the disease. Nevertheless, many patients display either intrinsic or acquired resistance to these drugs; hence, major research goals are to better understand the underlying causes of resistance, and to develop new therapeutic strategies that boost the impact of EGFR/ErbB inhibitors. In this review, we first summarize current standard use of EGFR inhibitors in the context of SCCHN, and described new agents targeting EGFR currently moving through pre-clinical and clinical development. We then discuss how changes in other transmembrane receptors, including IGF1R, c-Met, and TGF-β, can confer resistance to EGFR-targeted inhibitors, and discuss new agents targeting these proteins. Moving downstream, we discuss critical EGFR-dependent effectors, including PLC-γ; PI3K and PTEN; SHC, GRB2, and RAS and the STAT proteins, as factors in resistance to EGFR-directed inhibitors and as alternative targets of therapeutic inhibition. We summarize alternative sources of resistance among cellular changes that target EGFR itself, through regulation of ligand availability, post-translational modification of EGFR, availability of EGFR partners for hetero-dimerization and control of EGFR intracellular trafficking for recycling versus degradation. Finally, we discuss new strategies to identify effective therapeutic combinations involving EGFR-targeted inhibitors, in the context of new system level data becoming available for analysis of individual tumors.

• Aurora A kinase activity influences calcium signaling in kidney cells.

  Authors: Olga V Plotnikova, Elena N Pugacheva, Erica A Golemis

  The Journal of cell biology. 06/2011; 193(6):1021-32.

  Most studies of Aurora A (AurA) describe it as a mitotic centrosomal kinase. However, we and others have recently identified AurA functions as diverse as control of ciliary resorption, cellMost studies of Aurora A (AurA) describe it as a mitotic centrosomal kinase. However, we and others have recently identified AurA functions as diverse as control of ciliary resorption, cell differentiation, and cell polarity control in interphase cells. In these activities, AurA is transiently activated by noncanonical signals, including Ca(2+)-dependent calmodulin binding. These and other observations suggested that AurA might be involved in pathological conditions, such as polycystic kidney disease (PKD). In this paper, we show that AurA is abundant in normal kidney tissue but is also abnormally expressed and activated in cells lining PKD-associated renal cysts. PKD arises from mutations in the PKD1 or PKD2 genes, encoding polycystins 1 and 2 (PC1 and PC2). AurA binds, phosphorylates, and reduces the activity of PC2, a Ca(2+)-permeable nonselective cation channel and, thus, limits the amplitude of Ca(2+) release from the endoplasmic reticulum. These and other findings suggest AurA may be a relevant new biomarker or target in the therapy of PKD.

• Interaction trap/two-hybrid system to identify interacting proteins.

  Authors: Erica A Golemis, Ilya Serebriiskii, Russell L Finley, Mikhail G Kolonin, Jeno Gyuris, Roger Brent

  Current protocols in neuroscience / editorial board, Jacqueline N. Crawley ... [et al.]. 04/2011; Chapter 4:Unit 4.4.

  The yeast two-hybrid method (or interaction trap) is a powerful technique for detecting protein interactions. The procedure is performed using transcriptional activation of a dual reporter system inThe yeast two-hybrid method (or interaction trap) is a powerful technique for detecting protein interactions. The procedure is performed using transcriptional activation of a dual reporter system in yeast to identify interactions between a protein of interest (the bait protein) and the candidate proteins for interaction. The method can be used to screen a protein library for interactions with a bait protein or to test for association between proteins that are expected to interact based on prior evidence. Interaction mating facilitates the screening of a library with multiple bait proteins.

• NEDD9 and BCAR1 negatively regulate E-cadherin membrane localization, and promote E-cadherin degradation.

  Authors: Nadezhda Tikhmyanova, Erica A Golemis

  PloS one. 01/2011; 6(7):e22102.

  The Cas scaffolding proteins (NEDD9/HEF1/CAS-L, BCAR1/p130Cas, EFSSIN, and HEPL/CASS4) regulate cell migration, division and survival, and are often deregulated in cancer. High BCAR1 expression isThe Cas scaffolding proteins (NEDD9/HEF1/CAS-L, BCAR1/p130Cas, EFSSIN, and HEPL/CASS4) regulate cell migration, division and survival, and are often deregulated in cancer. High BCAR1 expression is linked to poor prognosis in breast cancer patients, while upregulation of NEDD9 contributes to the metastatic behavior of melanoma and glioblastoma cells. Our recent work knocking out the single Drosophila Cas protein, Dcas, identified a genetic interaction with E-cadherin. As E-cadherin is often downregulated during epithelial-mesenchymal transition (EMT) prior to metastasis, if such an activity was conserved in mammals it might partially explain how Cas proteins promote aggressive tumor behavior. We here establish that Cas proteins negatively regulate E-cadherin expression in human mammary cells. Cas proteins do not affect E-cadherin transcription, but rather, BCAR1 and NEDD9 signal through SRC to promote E-cadherin removal from the cell membrane and lysosomal degradation. We also find mammary tumors arising in MMTV-polyoma virus T-antigen mice have enhanced junctional E-cadherin in a Nedd9(-/-) background. Cumulatively, these results suggest a new role for Cas proteins in cell-cell adhesion signaling in cancer.

• Chemotherapy and signaling: How can targeted therapies supercharge cytotoxic agents?

  Authors: Tetyana V Bagnyukova, Ilya G Serebriiskii, Yan Zhou, Elizabeth A Hopper-Borge, Erica A Golemis, Igor Astsaturov

  Cancer biology & therapy. 11/2010; 10(9):839-53.

  In recent years, oncologists have begun to conclude that chemotherapy has reached a plateau of efficacy as a primary treatment modality, even if toxicity can be effectively controlled. EmergingIn recent years, oncologists have begun to conclude that chemotherapy has reached a plateau of efficacy as a primary treatment modality, even if toxicity can be effectively controlled. Emerging specific inhibitors of signaling and metabolic pathways (i.e., targeted agents) contrast with traditional chemotherapy drugs in that the latter primarily interfere with the DNA biosynthesis and the cell replication machinery. In an attempt to improve on the efficacy, combination of targeted drugs with conventional chemotherapeutics has become a routine way of testing multiple new agents in early phase clinical trials. This review discusses the recent advances including integrative systematic biology and RNAi approaches to counteract the chemotherapy resistance and to buttress the selectivity, efficacy and personalization of anti-cancer drug therapy.

• Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking NEDD9.

  Authors: Mahendra K Singh, Eugene Izumchenko, Andres J Klein-Szanto, Brian L Egleston, Marina Wolfson, Erica A Golemis

  Cancer research. 10/2010; 70(21):8907-16.

  Elevated expression of the NEDD9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the mouseElevated expression of the NEDD9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyVT) genetic model is delayed by a Nedd9(-/-) genotype. These activities arise from the role of NEDD9 in assembling complexes and supporting activity of cancer signaling proteins, including FAK, Src, Shc, and AKT, and would support evaluation of NEDD9 expression as an unambiguous biomarker for tumor aggressiveness. However, we here show that despite the initial delay in tumor growth, cells derived from MMTV-PyVT;Nedd9(-/-) tumors are characteristically hyperaggressive versus MMTV-PyVT;Nedd9(+/+) cells in anchorage-independent growth, in growth on three-dimensional matrix produced by tumor-associated fibroblasts, and in formation of tumors after mammary orthotopic reinjection and of lung metastases after tail vein injection. This reversal suggests the specific selection of MMTV-PyVT;Nedd9(-/-) cells for growth in an in vivo microenvironment. Indeed, MMTV-PyVT;Nedd9(-/-) cells have increased cell cycle, centrosomal, and mitotic defects, phenotypes compatible with the increased selection of these cells for aggressive growth. Intriguingly, in spite of their aggressive phenotype, MMTV-PyVT;Nedd9(-/-) cells persistently have low levels of Src activation and are hypersensitive to the Src kinase inhibitor dasatinib. These studies identify NEDD9 as a complex modulator of different aspects of mammary tumor growth.

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• TACCing on new functions for the TSC2 tumor suppressor.

  Authors: Erica A Golemis

  Cell cycle (Georgetown, Tex.). 04/2010; 9(7):1232-3.

• Rapid calcium-dependent activation of Aurora-A kinase.

  Authors: Olga V Plotnikova, Elena N Pugacheva, Roland L Dunbrack, Erica A Golemis

  Nature communications. 01/2010; 1:64.

  Oncogenic hyperactivation of the mitotic kinase Aurora-A (AurA) in cancer is associated with genomic instability. Increasing evidence indicates that AurA also regulates critical processes in normalOncogenic hyperactivation of the mitotic kinase Aurora-A (AurA) in cancer is associated with genomic instability. Increasing evidence indicates that AurA also regulates critical processes in normal interphase cells, but the source of such activity has been obscure. We report here that multiple stimuli causing release of Ca(2+) from intracellular endoplasmic reticulum stores rapidly and transiently activate AurA, without requirement for second messengers. This activation is mediated by direct Ca(2+)-dependent calmodulin (CaM) binding to multiple motifs on AurA. On the basis of structure-function analysis and molecular modelling, we map two primary regions of CaM-AurA interaction to unfolded sequences in the AurA N- and C-termini. This unexpected mechanism for AurA activation provides a new context for evaluating the function of AurA and its inhibitors in normal and cancerous cells.

• Dcas supports cell polarization and cell-cell adhesion complexes in development.

  Authors: Nadezhda Tikhmyanova, Alexei V Tulin, Fabrice Roegiers, Erica A Golemis

  PloS one. 01/2010; 5(8):e12369.

  Mammalian Cas proteins regulate cell migration, division and survival, and are often deregulated in cancer. However, the presence of four paralogous Cas family members in mammals (BCAR1/p130Cas,Mammalian Cas proteins regulate cell migration, division and survival, and are often deregulated in cancer. However, the presence of four paralogous Cas family members in mammals (BCAR1/p130Cas, EFS/Sin1, NEDD9/HEF1/Cas-L, and CASS4/HEPL) has limited their analysis in development. We deleted the single Drosophila Cas gene, Dcas, to probe the developmental function of Dcas. Loss of Dcas had limited effect on embryonal development. However, we found that Dcas is an important modulator of the severity of the developmental phenotypes of mutations affecting integrins (If and mew) and their downstream effectors Fak56D or Src42A. Strikingly, embryonic lethal Fak56D-Dcas double mutant embryos had extensive cell polarity defects, including mislocalization and reduced expression of E-cadherin. Further genetic analysis established that loss of Dcas modified the embryonal lethal phenotypes of embryos with mutations in E-cadherin (Shg) or its signaling partners p120- and beta-catenin (Arm). These results support an important role for Cas proteins in cell-cell adhesion signaling in development.

• Synthetic lethal screen of an EGFR-centered network to improve targeted therapies.

  Authors: Igor Astsaturov, Vladimir Ratushny, Anna Sukhanova, Margret B Einarson, Tetyana Bagnyukova, Yan Zhou, Karthik Devarajan, Joshua S Silverman, Nadezhda Tikhmyanova, Natalya Skobeleva, Anna Pecherskaya, Rochelle E Nasto, Catherine Sharma, Sandra A Jablonski, Ilya G Serebriiskii, Louis M Weiner, Erica A Golemis

  Science signaling. 01/2010; 3(140):ra67.

  Intrinsic and acquired cellular resistance factors limit the efficacy of most targeted cancer therapeutics. Synthetic lethal screens in lower eukaryotes suggest that networks of genes closely linkedIntrinsic and acquired cellular resistance factors limit the efficacy of most targeted cancer therapeutics. Synthetic lethal screens in lower eukaryotes suggest that networks of genes closely linked to therapeutic targets would be enriched for determinants of drug resistance. We developed a protein network centered on the epidermal growth factor receptor (EGFR), which is a validated cancer therapeutic target, and used small interfering RNA screening to comparatively probe this network for proteins that regulate the effectiveness of both EGFR-targeted agents and nonspecific cytotoxic agents. We identified subnetworks of proteins influencing resistance, with putative resistance determinants enriched among proteins that interacted with proteins at the core of the network. We found that clinically relevant drugs targeting proteins connected in the EGFR network, such as protein kinase C or Aurora kinase A, or the transcriptional regulator signal transducer and activator of transcription 3 (STAT3), synergized with EGFR antagonists to reduce cell viability and tumor size, suggesting the potential for a direct path to clinical exploitation. Such a focused approach can potentially improve the coherent design of combination cancer therapies.

• NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development.

  Authors: Eugene Izumchenko, Mahendra K Singh, Olga V Plotnikova, Nadezhda Tikhmyanova, Joy L Little, Ilya G Serebriiskii, Sachiko Seo, Mineo Kurokawa, Brian L Egleston, Andres Klein-Szanto, Elena N Pugacheva, Richard R Hardy, Marina Wolfson, Denise C Connolly, Erica A Golemis

  Cancer research. 10/2009;

  In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies haveIn the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9(-/-) mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9(+/+) and Nedd9(-/-) tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness. [Cancer Res 2009;69(18):7198-206].

• Interaction trap/two-hybrid system to identify interacting proteins.

  Authors: Erica A Golemis, Ilya Serebriiskii, Russell L Finley, Mikhail G Kolonin, Jeno Gyuris, Roger Brent

  Current protocols in protein science / editorial board, John E. Coligan ... [et al.]. 09/2009; Chapter 19:Unit19.2.

  The yeast two-hybrid method (or interaction trap) is a powerful technique for detecting protein interactions. The procedure is performed using transcriptional activation of a dual reporter system inThe yeast two-hybrid method (or interaction trap) is a powerful technique for detecting protein interactions. The procedure is performed using transcriptional activation of a dual reporter system in yeast to identify interactions between a protein of interest (the bait protein) and the candidate proteins for interaction. The method can be used to screen a protein library for interactions with a bait protein or to test for association between proteins that are expected to interact based on prior evidence. Interaction mating facilitates the screening of a library with multiple bait proteins.

• Mechanisms of tumor resistance to EGFR-targeted therapies.

  Authors: Elizabeth A Hopper-Borge, Rochelle E Nasto, Vladimir Ratushny, Louis M Weiner, Erica A Golemis, Igor Astsaturov

  Expert opinion on therapeutic targets. 04/2009; 13(3):339-62.

  BACKGROUND: Much effort has been devoted to development of cancer therapies targeting EGFR, based on its role in regulating cell growth. Small-molecule and antibody EGFR inhibitors have clinicalBACKGROUND: Much effort has been devoted to development of cancer therapies targeting EGFR, based on its role in regulating cell growth. Small-molecule and antibody EGFR inhibitors have clinical roles based on their efficacy in a subset of cancers, generally as components of combination therapies. Many cancers are either initially resistant to EGFR inhibitors or become resistant during treatment, limiting the efficacy of these reagents. OBJECTIVE/METHODS: To review cellular resistance mechanisms to EGFR-targeted therapies. RESULTS/CONCLUSIONS: The best validated of these mechanisms include activation of classic ATP-binding casette (ABC) multidrug transporters; activation or mutation of EGFR; and overexpression or activation of signaling proteins operating in relation to EGFR. We discuss current efforts and potential strategies to override these sources of resistance. We describe emerging systems-biology-based concepts of alternative resistance to EGFR-targeted therapies, and discuss their implications for use of EGFR-targeted and other targeted therapies.

• Primary cilia and the cell cycle.

  Authors: Olga V Plotnikova, Elena N Pugacheva, Erica A Golemis

  Methods in cell biology. 01/2009; 94:137-60.

  Cilia are microtubule-based structures that protrude from the cell surface and function as sensors for mechanical and chemical environmental cues that regulate cellular differentiation or division.Cilia are microtubule-based structures that protrude from the cell surface and function as sensors for mechanical and chemical environmental cues that regulate cellular differentiation or division. In metazoans, ciliary signaling is important during organismal development and in the homeostasis controls of adult tissues, with receptors for the Hedgehog, platelet derived growth factor (PDGF), Wnt, and other signaling cascades arrayed and active along the ciliary membrane. In normal cells, cilia are dynamically regulated during cell cycle progression: present in G0 and G1 cells, and usually in S/G2 cells, but almost invariably resorbed before mitotic entry, to reappear post-cytokinesis. This periodic resorption and reassembly of cilia, specified by the intrinsic cell cycle the intrinsic cell cycle machinery, influences the susceptibility of cells to the influence of extrinsic signals with cilia-associated receptors. Pathogenic conditions of mammals associated with loss of or defects in ciliary integrity include a number of developmental disorders, cystic syndromes in adults, and some cancers. With the continuing expansion of the list of human diseases associated with ciliary abnormalities, the identification of the cellular mechanisms regulating ciliary growth and disassembly has become a topic of intense research interest. Although these mechanisms are far from being understood, a number of recent studies have begun to identify key regulatory factors that may begin to offer insight into disease pathogenesis and treatment. In this chapter we will discuss the current state of knowledge regarding cell cycle control of ciliary dynamics, and provide general methods that can be applied to investigate cell cycle-dependent ciliary growth and disassembly.

• Cell cycle-dependent ciliogenesis and cancer.

  Authors: Olga V Plotnikova, Erica A Golemis, Elena N Pugacheva

  Cancer research. 05/2008; 68(7):2058-61.

  In mammals, most cell types have primary cilia, protruding structures involved in sensing mechanical and chemical signals from the extracellular environment that act as major communication hubs forIn mammals, most cell types have primary cilia, protruding structures involved in sensing mechanical and chemical signals from the extracellular environment that act as major communication hubs for signaling controlling cell differentiation and polarity. The list of clinical disorders associated with ciliary dysfunction has expanded from polycystic kidney disease to include many others. Transformed cells commonly lack cilia, but whether this lack is cause or consequence of transformation is not well understood. Here we discuss work addressing recently identified actions of the cancer-promoting proteins Aurora A and HEF1/NEDD9/CAS-L at cilia. Together with older studies, this work suggests that loss of cilia in cancer may contribute to the insensitivity of cancer cells to environmental repressive signals, based in part on derangement of cell cycle checkpoints governed by cilia and centrosomes.

• A Novel Cas Family Member, HEPL, Regulates FAK and Cell Spreading.

  Authors: Mahendra K Singh, Disha Dadke, Emmanuelle Nicolas, Ilya G Serebriiskii, Sinoula Apostolou, Adrian Canutescu, Brian L Egleston, Erica A Golemis

  Molecular biology of the cell. 05/2008; 19(4):1627-36.

  For over a decade, p130Cas/BCAR1, HEF1/NEDD9/Cas-L, and Efs/Sin have defined the Cas (Crk-associated substrate) scaffolding protein family. Cas proteins mediate integrin-dependent signals at focalFor over a decade, p130Cas/BCAR1, HEF1/NEDD9/Cas-L, and Efs/Sin have defined the Cas (Crk-associated substrate) scaffolding protein family. Cas proteins mediate integrin-dependent signals at focal adhesions, regulating cell invasion and survival; at least one family member, HEF1, regulates mitosis. We here report a previously undescribed novel branch of the Cas protein family, designated HEPL (for HEF1-Efs-p130Cas-like). The HEPL branch is evolutionarily conserved through jawed vertebrates, and HEPL is found in some species lacking other members of the Cas family. The human HEPL mRNA and protein are selectively expressed in specific primary tissues and cancer cell lines, and HEPL maintains Cas family function in localization to focal adhesions, as well as regulation of FAK activity, focal adhesion integrity, and cell spreading. It has recently been demonstrated that upregulation of HEF1 expression marks and induces metastasis, whereas high endogenous levels of p130Cas are associated with poor prognosis in breast cancer, emphasizing the clinical relevance of Cas proteins. Better understanding of the complete protein family should help inform prediction of cancer incidence and prognosis.

• Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells.

  Authors: Ilya Serebriiskii, Remedios Castelló-Cros, Acacia Lamb, Erica A Golemis, Edna Cukierman

  Matrix biology : journal of the International Society for Matrix Biology. 04/2008;

  Recent studies have emphasized the importance of cellular microenvironment in modulating cell growth and signaling. In vitro, collagen matrices, Matrigel, and other synthetic support systems haveRecent studies have emphasized the importance of cellular microenvironment in modulating cell growth and signaling. In vitro, collagen matrices, Matrigel, and other synthetic support systems have been used to simulate in vivo microenvironments, and epithelial cells grown in these matrices manifest significant differences in proliferation, differentiation, response to drugs, and other parameters. However, these substrates do not closely resemble the mesenchymal microenvironment that is typically associated with advanced carcinomas in vivo, which is produced to a large extent by fibroblasts. In this study, we have evaluated the ability of a fibroblast-derived three-dimensional matrix to regulate the growth of a panel of 11 human tumor epithelial cell lines. Although proliferative and morphological responses to three-dimensional cues segregated independently, general responsiveness to the matrix correlated with the ability of matrix to influence drug responses. Fibroblast-derived three-dimensional matrix increased beta1-integrin-dependent survival of a subset of human cancer cell lines during taxol treatment, while it sensitized or minimally influenced survival of other cells. beta1-integrin-dependent changes in cell resistance to taxol did not correlate with the degree of modulation of FAK and Akt, implying that additional signaling factors are involved. Based on these results, we propose that these matrices potentially have value as in vitro drug screening platforms.

• Selective Raf inhibition in cancer therapy.

  Authors: Vladimir Khazak, Igor Astsaturov, Ilya G Serebriiskii, Erica A Golemis

  Expert opinion on therapeutic targets. 01/2008; 11(12):1587-609.

  Over the past 5 years, the Raf kinase family has emerged as a promising target for protein-directed cancer therapy development. The goal of this review is to first provide a concise summary of theOver the past 5 years, the Raf kinase family has emerged as a promising target for protein-directed cancer therapy development. The goal of this review is to first provide a concise summary of the data validating Raf proteins as high-interest therapeutic targets. The authors then outline the mode of action of Raf kinases, emphasizing how Raf activities and protein interactions suggest specific approaches to inhibiting Raf. The authors then summarize the set of drugs, antisense reagents and antibodies available or in development for therapeutically targeting Raf or Raf-related proteins, as well as existing strategies combining these and other therapeutic agents. Finally, the authors discuss recent results from systems biology analyses that have the potential to increasingly guide the intelligent selection of combination therapies involving Raf-targeting agents and other therapeutics.

• A new central scaffold for metastasis: parsing HEF1/Cas-L/NEDD9.

  Authors: Geraldine M O'Neill, Sachiko Seo, Ilya G Serebriiskii, Stuart R Lessin, Erica A Golemis

  Cancer research. 11/2007; 67(19):8975-9.

  Greater understanding of metastasis is required to improve cancer treatment outcomes. Recently, changes in expression of the scaffold protein HEF1/CAS-L/NEDD9 were found to be a potent prometastaticGreater understanding of metastasis is required to improve cancer treatment outcomes. Recently, changes in expression of the scaffold protein HEF1/CAS-L/NEDD9 were found to be a potent prometastatic stimulus in melanoma and other cancers. Mechanistic studies suggest diverse cellular roles of HEF1 and highlight its importance in the response to extracellular cues that drive invasion and metastasis. As a metastatic "hub" for signaling in cancer, HEF1 may provide a useful target for drug discovery efforts.