פרופ' חוה גיל-חן
Research
Cytoskeletal remodeling is a fundamental biological process that requires precise coordination of several molecular pathways and physical forces. From single-cell organisms searching for nutrients to complex neurons searching for synaptic partners, at some point in their life cycle most cells must remodel their cytoskeleton to change their shape or move. Understanding how cells encounter and sum a multitude of signals in their complex extracellular milieu and translate those signals into the complex processes that dictate whether a cell changes its shape or moves is of great importance to biology. The molecular details of these processes and the complex signaling networks that regulate them are only starting to be revealed at present. Research in our laboratory focuses on cytoskeletal signaling by non-receptor tyrosine kinases, cellular relays that translate information from cell surface growth factor and adhesion receptors to promote downstream events such as enzymatic activities, cytoskeletal reorganization, gene expression, and synaptic plasticity. We use a multidisciplinary approach, which combines advanced molecular and cellular biology methods, in vitro and in vivo RNAi-mediated genetic manipulations, transgenic and knockout mice models, cutting-edge in vivo methods, high-resolution fluorescent, and intravital imaging, and in vivo transcriptomics/proteomics followed by integrated bioinformatics and systems biology analyses, to understand and characterize, at the molecular, cellular, and whole-organism levels, the cytoskeletal signaling networks that regulate normal physiological processes and their modifications leading to human disease. A better understanding of the cytoskeletal mechanisms and signaling pathways that regulate and execute these processes could suggest novel clinical targets and strategies for the diagnosis and treatment of human diseases such as cancer metastasis, brain and behavior, psychiatric disorders, and Alzheimer’s disease, and is a fundamental goal of our research.
Publications
A. Peretz*, H. Gil-Henn*, A. Sobko, V. Shinder, B. Attali and A. Elson (2000). Hypomyelination and increased activity of voltage gated potassium channels in mice lacking protein tyrosine phosphatase e. EMBO J. 19, 4036-4045.
Hava Gil-Henn, Gloria Volohonski, Hila Toledano-Katchalski, Shilpa Gandre and Ari Elson (2000). Generation of novel cytoplasmic forms of protein tyrosine phosphatase epsilon by proteolytic cleavage and translational control. Oncogene 19, 4375-4384.
Hava Gil-Henn, Gloria Volohonski and Ari Elson (2001). Regulation of protein tyrosine phosphatases a and e by calpain-mediated proteolytic cleavage. J. Biol. Chem. 276, 31772-31779.
Hava Gil-Henn, Asher Peretz, Alexander Sobko, Vera Shinder, Bernard Attali and Ari Elson (2001). Wild-type and novel forms of PTPe regulate myelination by affecting voltage gated potassium channels. Invited article in: “Protein Modules in Cellular Signaling” pp. 202-213. Heilmeyer, L.M.G. jr. and Friedrich, P. (eds.), IOS Press, Amsterdam.
Hava Gil-Henn and Ari Elson (2003). Tyrosine phosphatase Epsilon activates Src and supports the transformed phenotype of Neu-induced mammary tumor cells. J. Biol. Chem. 278, 15579-86.
Hila Toledano-Katchalski, Judith Kraut, Tal Sines, Shira Granot-Attas, Galit Shohat, Hava Gil-Henn, Yuval Yung and Ari Elson (2003). Protein tyrosine phosphatase Epsilon inhibits signaling by mitogen activated protein kinases. Mol. Cancer Research 1, 541-550.
F. Levitin, O. Stern, M. Weiss, H. Gil-Henn, R. Ziv, Z. Prokocimer, N.I. Smorodinsky, D.B. Rubinstein, D.H. Wreschner (2005). The MUC1 SEA module is a self-cleaving domain. J. Biol. Chem. 280, 33374-86.
Hava Gil-Henn, Olivier Destaing, Angela Bruzzaniti, Natalie Sims, Kazuhiro Aoki, Neil Alles, Archana Sanjay, Lynn Neff, Roland Baron, and Joseph Schlessinger (2006). Pyk2-/- mice are osteopetrotic due to defective regulation of microtubules and actin in osteoclasts. Journal of Bone and Mineral Research 21, S67.
Hava Gil-Henn, Olivier Destaing, Natalie A. Sims, Kazuhiro Aoki, Neil Alles, Lynn Neff, Archana Sanjay, Angela Bruzzaniti, Pietro De Camilli, Roland Baron, and Joseph Schlessinger. (2007) Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2-/- mice. J. Cell Biol. 178, 1053-64.
Lu Wang, Ioannis Tassiulas, Kyung-Hyun Park-Min, Alicia C. Reid, Hava Gil-Henn, Joseph Schlessinger, Roland Baron, Jillian Zhang, and Lionel B. Ivashkiv. (2007) Regulation of macrophage Jak activation and STAT1 tyrosine phosphorylation by ITAM-associated receptors is mediated by calcium-dependent CaMK and Pyk2. Nature Immunology 9, 186-93.
Matthew Oser, Christopher Mader, Hava Gil-Henn, Marco Magalhaes, Jose Javier Bravo-Cordero, Anthony Koleske, and John Condeelis (2010). Specific tyrosine phosphorylation sites on cortactin regulate NCK1-dependent actin polymerization in invadopodia. Journal of Cell Science 123, 3662-73.
Christopher Mader, Matthew Oser, Marco Magalhaes, Jose Javier Bravo-Cordero, John Condeelis, Anthony Koleske, and Hava Gil-Henn (2011). A Src-Arg kinase signaling relay regulates breast cancer invasiveness by controlling invadopodium maturation and function. Cancer Research 71(5), 1730-41.
Marco Magalhaes, Daniel Larson, Christopher Mader, Jose Javier Bravo-Cordero, Hava Gil-Henn, Matthew Oser, Xiaoming Chen, Anthony Koleske, and John Condeelis (2011). Cortactin phosphorylation regulates cell invasion through a pH dependent pathway. The Journal of Cell Biology 195(5) 903-20.
Hadas Sibony-Benyamini and Hava Gil-Henn (2012). Invadopodia: the leading force. European Journal of Cell Biology 91, 896-901 (invited review).
Hava Gil-Henn, Antonia Patsialou, Yarong Wang, Michael Sloan Warren, John Condeelis, and Anthony Koleske (2013). Arg/Abl2 promotes invasion and attenuates proliferation of breast cancer in vivo. Oncogene 32, 2622-30.
Nir Ben-Chetrit, David Chetrit, Maicol Mancini, Tomer Itkin, Silvia Carvalho, Hadas Cohen-Dvashi, Wolfgang Koestller, Moshit Lindzen, Ziv Shulman, Raanan Margalit, Dalia Seger, Daniela A. Ferraro, Ziv Shulman, Martin Bernstein, Hava Gil-Henn, Tsvee Lapidot, Ronen Alon, Marc Symons, Fernando Schmitt, Marcelo Ehrlich, and Yosef Yarden (2015). Synaptojanin 2 is a druggable mediator of metastasis, and the gene is overexpressed and amplified in breast cancer. Science Signaling 8(360); ra7.
Roman Samsonov, Vladimir Burdakov, Tatiana Shtam, Zamira Radzhabova, Dmitry Vasilyev, Evgenia Tsyrlina, Sergey Titov, Michail Ivanov, Lev Berstein, Michael Filatov, Nikolay Kolesnikov, Hava Gil-Henn, and Anastasia Malek (2016). Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer. Tumor Biology 37(9), 12011-12021.
Stefanie Lapetina and Hava Gil-Henn (2017). A guide to simple, direct, and quantitative in vitro binding assays. Journal of Biological Methods 4(1) e62, 1-11.
Rosenberg BJ, Gil-Henn H, Mader CC, Halo T, Yin T, Condeelis J, Machida K, Wu YI, Koleske AJ (2017). Phosphorylated cortactin recruits Vav2 guanine nucleotide exchange factor to activate Rac3 and promote invadopodial function in invasive breast cancer cells. Molecular Biology of the Cell 28(10), 1347-1360.
Manikoth Ayyathan D, Ilić N, Gil-Henn H, Blank M. (2017). Generation of SMURF2 knockout human cells using the CRISPR/Cas9 system. Analytical Biochemistry 531, 56-59.
Tomer Meirson, Abraham O. Samson, and Hava Gil-Henn (2017). An in silico high-throughput screen identifies potential selective inhibitors for the non-receptor tyrosine kinase Pyk2. Drug Design, Development, and Therapy 11, 1535-1557.
Alessandro Genna, Stefanie Lapetina, Nikola Lukic, Shams Twafra, Tomer Meirson, Ved P. Sharma, John S. Condeelis, and Hava Gil-Henn (2018). Pyk2 and FAK differentially regulate invadopodia formation and function in breast cancer cells. The Journal of Cell Biology 217, 375-395.
Alessandro Genna and Hava Gil-Henn (2018). FAK family kinases: the Yin and Yang of cancer cell invasiveness. Molecular and Cellular Oncology 5(4), e1449584, 1-3 (invited author’s view).
Tomer Meirson, Alessandro Genna, Nikola Lukic, Tetiana Makhnii, Joel Alter, Ved P. Sharma, Yarong Wang, Abraham O. Samson, John S. Condeelis, and Hava Gil-Henn (2018). Using ABL kinase inhibitors to block breast cancer metastasis. Oncotarget 9(31), 22158-22183.
Cameron Goertzen, Hayder Mahdi, Catherine Laliberte, Tomer Meirson, Denise Eymael, Hava Gil-Henn, and Marco Magalhaes (2018). Oral inflammation promotes oral squamous cell carcinoma invasion. Oncotarget 9(49), 29047-29063.
Tomer Meirson and Hava Gil-Henn (2018). Targeting invadopodia for blocking breast cancer metastasis. Drug Resistance Updates 39, 1-17 (invited review).
Hasini Jayatilaka, Fatima Umanzor, Vishwesh Shah, Tomer Meirson, Alexandra Sneider, Gabriella Russo, Bartholomew Starich, Paranay Tyle, Jerry Lee, Shyam Khatau, Hava Gil-Henn, and Denis Wirtz (2018). Cell density-mediated expression of matrix metalloproteinases. Oncotarget 9(66), 32556-32569.
Baruh Polis, Kolluru Devi Dutt Srikanth, Evan Elliott, Hava Gil-Henn, and Abraham O. Samson (2018). L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease. Neurotherapeutics 15(4), 1036-1054.
Kolluru D. Srikanth, Tomer Meirson, Dev Sharan Sams, and Hava Gil-Henn (2018). FAK family kinases in brain health and disease. Journal of Molecular and Clinical Medicine 1(3), 177-190.
Baruh Polis and Hava Gil-Henn (2019). Commentary on Giralt et al.: PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer’s disease. Experimental Neurology 311, 313-317.
Shtam Tatiana, Naryzhny Stanislav, Samsonov Roman, Karasik David, Mizgirev Igor, Kopylov Artur, Petrenko Elena, A. Zabrodskaya Yana, Kamyshinsky Roman, Gil-Henn Hava*, and Malek Anastasia* (2019). Plasma exosomes stimulate breast cancer motility and invasion via surface interaction and activation of FAK. Breast Cancer Research and Treatment 174(1), 129-141.
* Co-corresponding authors equally contributed.
Baruh Polis, Kolluru D Srikanth, Vyacheslav Gurevich, Hava Gil-Henn, and Abraham O. Samson (2019). L-Norvaline, a new therapeutic agent against Alzheimer’s disease. Neural Regen Res. 14(9), 1562-1572.
Liat Ninio, Abraham Nissani#, Tomer Meirson#, Tom Domovitch, Alessandro Genna, Shams Twafra, Kolluru D. Srikanth, Roba Dabour, Erez Avraham, Ateret Davidovich, Hava Gil-Henn*, and Meital Gal-Tanamy* (2019). Hepatitis C virus induces hepatocellular carcinoma invasiveness via generation and activation of invadopodia. Cells 8(11), 1395.
* Co-corresponding authors equally contributed.
Tomer Meirson, David Bomze, Liron Kahlon, Hava Gil-Henn, and Abraham O. Samson (2020). A helical lock and key model of polyproline II conformation. Bioinformatics, pii: btz527.
Tomer Meirson, Hava Gil-Henn, and Abraham O. Samson (2020). Invasion and metastasis: the elusive hallmark of cancer. Oncogene, 39(9); 2024-2026.
Polis B, Srikanth KD, Gurevich V, Bloch N, Gil-Henn H, Samson AO (2020). Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer's Disease Mice. Int J Mol Sci. 21(3):1133.
Alonzo J. Whyte, Gracy Trinoskey-Rice, Rachel A. Davies, Ellen P. Woon, Stephanie L. Foster, Lauren P. Shapiro, Kolluru D. Srikanth, Hava Gil-Henn, and Shannon L. Gourley (2021). Integrin and dendritic spine loss in the orbitofrontal cortex trigger reward-seeking behaviors and impair amygdala-dependent action. Journal of Neuroscience 41(27), 5923-5936.
Ghosh S, Nataraj NB, Noronha A, Patkar S, Sekar A, Mukherjee S, Winograd-Katz S, Kramarski L, Verma A, Lindzen M, Garcia DD, Green J, Eisenberg G, Gil-Henn H, Basu A, Lender Y, Weiss S, Oren M, Lotem M, Geiger B, Ruppin E, Yarden Y. (2021). PD-L1 recruits phospholipase C and enhances EGFR signaling in lung tumors harboring mutant forms of EGFR (2021). Cell Reports 35 (8): 109181.
Jonathan Solomon, Magdalena Raška, Daniel Rösel, Jan Brábek, and Hava Gil-Henn (2021). Are we ready for migrastatics? Cells 10(8), 1845.
Trishna Saha, Jonathan Solomon, Abraham O. Samson, and Hava Gil-Henn (2021). Invasion and metastasis as a central hallmark of breast cancer. Journal of Clinical Medicine 10(16), 3498 (invited review).
Trishna Saha and Hava Gil-Henn (2021). Invadopodia, a kingdom of non-receptor tyrosine kinases. Cells 10(8), 2037.
Nikola Lukic, Stefanie Lapetina, Kolluru D. Srikanth, Shams Twafra, Jonathan Solomon, and Hava Gil-Henn (2021). Pyk2 regulates cell edge protrusion dynamics by interacting with Crk. Molecular
Biology of the Cell Nov 1;32(21):ar17.
* Cover image for the November 1st issue was chosen from this paper.
Nikola Lukic, Trishna Saha, Stefanie Lapetina, Gilad Lehmann, Anthony J. Koleske, and Hava Gil-Henn (2021). Measuring cell-edge protrusion dynamics during spreading by using live-cell microscopy. JoVE Nov 1;(177):10.3791/63157.
Seung-Uon Shin, Hyun-Mi Cho, Rathin Das, Hava Gil-Henn, Sundaram Ramakrishnan,
Ahmed Al Bayati, Stephen F. Carroll, Yu Zhang, Ankita P. Sankar, Christian Elledge, Augustin Pimentel, Marzenna Blonska, and Joseph D. Rosenblatt (2021). Inhibition of vasculogenic mimicry and angiogenesis by an anti-EGFR IgG1-human endostatin-P125A fusion protein reduces triple negative breast cancer metastases. Cells 10(11): 2904.
Shannon L. Gourley, Kolluru D. Srikanth, Ellen P. Woon, and Hava Gil-Henn (2021).
Pyk2 stabilizes striatal medium spine neuron structure and striatal-dependent action.
Cells 10(12):3442.
Trishna Saha Detroja, Hava Gil-Henn and Abraham Samson (2022). Text mining approach to identify hub genes of cancer metastasis and potential drug repurposing to target them. Journal of Clinical Medicine 11(8):2130.
Bisan Saleh, Kolluru D. Srikanth, Tal Sneh, Lambert Yue, Steven Pelech, Evan Elliott, and Hava Gil-Henn (2022). FAK-mediated signaling controls amyloid beta overload and learning and memory deficits in a mouse model of Alzheimer’s disease. International Journal of Molecular Sciences 23(16): 9055.
Shams Twafra, Chana G. Sokolik, Tal Sneh, Kolluru D. Srikanth, Tomer Meirson, Alessandro Genna, Jordan H. Chill, and Hava Gil-Henn (2023). A novel Pyk2-derived peptide inhibits invadopodia-mediated breast cancer metastasis. Oncogene 42(4): 278-292.
תאריך עדכון אחרון : 05/11/2023
