Songhai Chen, MD, PhD

Portrait
Associate Professor of Pharmacology
Associate Professor of Internal Medicine

Contact Information

Primary Office
2-250 BSB
Iowa City, IA 52242
319-384-4562

Lab
2-240 BSB
Iowa City, IA 52242
319-384-4563

Education

MD, Fujian Medical University
MS, Beijing Medical University (now Health Science Center, Peking University)
PhD, School of Medicine, University of New South Wales
Resident, Zhangzhou First Hospital, Dept of Internal Medicine, Fujian Province, China
Fellow, Biochemistry and Molecular Pharmacology, University of New South Wales, Sydney, Australia

Education/Training Program Affiliations

Interdisciplinary Graduate Program in Molecular Medicine, Medical Scientist Training Program

Research Summary

The broad goal of research in my lab is to define the function and regulation of heterotrimeric G proteins in leukocyte migration and tumor metastasis. The major focus of our research is to elucidate how G protein ß? subunits orchestrate the formation of specific signaling complexes to promote directional cell migration. Particularly, we are interested in understanding how Gß? functions are regulated by a group of novel interacting proteins, WD40 repeat-containing proteins, which we recently identified by a yeast two-hybrid screen. Free Gß? liberated from the activated Gi/o family of G proteins is a master regulator of signal transduction pathways that control chemokine-induced chemotaxis of diverse cells, ranging from neurons, leukocytes to tumor cells. Over the last decade, significant progress has been made in understanding how Gß? stimulates key signaling molecules such as PI3K? to promote cell migration. However, Gß? has diverse interacting proteins. How it coordinates the activation of various effectors in the highly specific temporal and spatial manner required for precise control of cell migration remains elusive. Our recent identification of WD40 repeat-containing proteins as novel Gß?- interacting proteins opens a new era in understanding the function and regulation of Gß? signaling. These proteins are predicted to form a similar ß-propeller structure with multiple surfaces as Gß (Figure). Therefore, like Gß?, they have the potential to assemble wide array of proteins to promote or inhibit Gß?-mediated signal transduction. Our studies from one of these proteins, receptor for activated C kinase 1 (RACK1), have yielded significant insights into the molecular basis for the interactions of WD40 repeat proteins with Gß?, and the role of these proteins in regulating Gß?-mediated cell migration. RACK1 is found to bind to a unique side-surface of Gß? through a novel protein-protein interaction, WD40-WD40 repeat interaction. Binding of RACK1 to Gß? selectively abrogates the activation of key signaling molecules, PI3K and PLCß, resulting in inhibition of leukocyte migration. RACK1 therefore may constitute an important negative regulator that controls the amplitude of leukocyte migration. Stemming from these exciting findings, our current research interests include the following areas: To investigate specific roles of RACK1-mediated negative regulation of leukocyte migration in physiological and pathological processes of immune responses; To determine the function of RACK1/ Gß? interaction in tumor metastasis, since chemokine receptors, which are frequently found to be overexpressed in tumor, also promote tumor cell migration through Gß?; To delineate the function of other Gß?-interacting WD40 repeat proteins in leukocyte migration and tumor metastasis; To understand the structural aspect of the WD40-WD40 repeat interaction by x-ray crystallography. To accomplish the outlined projects, we are using a combination of molecular and cellular techniques, animal models, fluorescence-based and FRET-based biophysical approaches. Moreover, we are using live cell imaging to monitor the complex and vivid process of cell migration. These studies could give rise to new insight into the signaling mechanisms governing leukocyte migration and tumor metastasis as well as uncovering new therapeutic targets.

Publications

Qian, Q., Zhang, Z., Orwig, A., Chen, S., Ding, W. X., Xu, Y., Kunz, R. C., Lind NRL,, Stamler, J. S. & Yang, L. (2018). S-Nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy. Diabetes, 67(2), 193-207. PMID: 29074597.

Ke, W., Ye, D., Mersch, K., Xu, H., Chen, S. & Lin, F. (2017). Gß1 is required for neutrophil migration in zebrafish. Developmental biology, 428(1), 135-147. PMID: 28554852.

Paudyal, P., Xie, Q., Vaddi, P. K., Henry, M. D. & Chen, S. (2017). Inhibiting G protein ß? signaling blocks prostate cancer progression and enhances the efficacy of paclitaxel. Oncotarget, 8(22), 36067-36081. PMID: 28415604.

Edvardson, S., Wang, H., Dor, T., Atawneh, O., Yaacov, B., Gartner, J., Cinnmon, Y., Chen, S. & Elpeleg, O. (2016). Microcephaly-dystonia due to mutated PLEKHG2 with impaired actin polymerization *co-corresponding authors. Neurogenetics, 17(1), 25-30. PMID: 26573021.

Ye, Y., Tang, X., Sun, Z. & Chen, S. (2016). Upregulated WDR26 serves as a scaffold to coordinate PI3K/AKT pathway-driven breast cancer cell growth, migration and invasion. Oncotarget, 7(14), 17854-69. PMID: 26895380.

Xie, Q., Klesney-Tait, J., Keck, K., Parlet, C., Borcherding, N., Kolb, R., Li, W., Tygrett, L., Waldschmidt, T., Olivier, A., Chen, S., Liu, G. H., Li, X. & Zhang, W. (2015). Characterization of a novel mouse model with genetic deletion of CD177. Protein & cell, 6(2), 117-26. PMID: 25359465.

Zhang, L., Blackwell, K., Workman, L. M., Chen, S., Pope, M. R., Janz, S. & Habelhah, H. (2015). RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-?B Activation and Lymphoma Survival. Mol Cell Biol, 35(19), 3324-38. PMID: 26195820.

Ye, Y., Sun, Z., Guo, A., Song, L. S., Grobe, J. & Chen, S. (2014). Ablation of the Gbeta3 gene does not affect blood pressure or metabolism, but cause bradycardia in mice. Cell Signal, 26(11), 2514-2520. PMID: 25093805.

Xi, H., Ye, D., Behra, M., Burgess, S., Chen, S. & Lin, F. (2014). Gß1 controls collective cell migration by regulating the protrusive activity of leader cells in the posterior lateral line primordium. Dev Biol, 385(2), 316-27. PMID: 24201188.

Runne, C., Chen, S. (2013). PLEKHG2 Promotes Heterotrimeric G Protein ß?-Stimulated Lymphocyte Migration via Rac and Cdc42 Activation and Actin Polymerization. *Recommended by Faculty 1000. Mol Cell Biol, 33(21), 4294-4307. PMID: 24001768.

Sun, Z., Smrcka, A. V. & Chen, S. (2013). WDR26 functions as a scaffolding protein to promote Gß?-mediated PLCß2 activation in leukocytes. J Biol Chem, 288(23), 16715-16725. PMID: 23625927.

Runne, C., Chen, S. (2013). WD40-repeat proteins control the flow of Gß? signaling for directional cell migration. Cell Adhesion & Migration, 7(2), 214-218. PMID: 23302952.

Sun, Z., Runne, C., Lin, F. & Chen, S. (2012). The Gß3 splice variant associated with the C825T gene polymorphism is an unstable and functionally inactive protein. Cell Signal, 24(12), 2349-2359. PMID: 22940628.

Xu, H., Kardash, E., Chen, S., Raz, E. & Lin, F. (2012). Gß? signaling controls the polarization of zebrafish primordial germ cells by regulating Rac activity. Development, 139(1), 57-62. PMID: 22096073.

Sun, Z., Tang, X., Lin, F. & Chen, S. (2011). The WD40-repeat protein WDR26 binds Gß?g and promotes Gß?-dependent signal transduction and leukocyte migration. J Biol Chem, 286(51), 43902-43912. PMID: 22065575.

Muniz, V. P., Barnes, J. M., Paliwal, S., Zhang, X., Tang, X., Chen, S., Zamba, G., Cullen, J. J., Meyerholz, D. K., Meyers, S., Davis, J. N., Grossman, S. R., Henry, M. D. & Quelle, D. E. (2011). The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis. Mol Cancer Res, 9(7), 867-877. PMID: 21636682.

Tang, X., Sun, Z., Runne, C., Madsen, J., Domann, F., Henry, M., Lin, F. & Chen, S. (2011). A critical role of Gß? in tumorigenesis and metastasis of breast cancer. J Biol Chem, 286(15), 13244-13254. PMID: 21349837.

Xu, H., Echemendia, N., Chen, S. & Lin, F. (2011). Identification and expression patterns of members of the protease-activated receptor (PAR) gene family during zebrafish development. Dev Dyn, 240(1), 278-287. PMID: 21181945.

Lin, F., Chen, S., Sepich, D. S., Panizzi, J. R., Clendenon, S. G., Marrs, J. A., Hamm, H. E. & Solnica-Krezel, L. (2009). Galpha12/13 regulate epiboly by inhibiting E-cadherin activity and modulating the actin cytoskeleton. J Cell Biol, 184(6), 909-921. PMID: 19307601.

Chen*, S., Lin, F., Shin, M. E., Wang, F., Shen, L. & Hamm*, H. E. (2008). RACK1 regulates directional cell migration by acting on G betagamma at the interface with its effectors PLC beta and PI3K gamma. *Corresponding authors. Mol Biol Cell, 19(9), 3909-3922. PMID: 18596232.

Chen, S., Hamm, H. E. (2006). DEP domains: More than just membrane anchors. Developmental Cell, 11(4), 436-8. PMID: 17011483.

Ding, J., Guzman, J. N., Tkatch, T., Chen, S., Goldberg, J. A., Eberg, P. J., Levitt, P., Wilson, C. J., Hamm, H. E. & Surmeier, D. J. (2006). RGS4-dependent attenuation of M(4) autoreceptor function in striatal cholinergic interneurons following dopamine depletion. Nat Neurosci, 9(6), 832-842. PMID: 16699510.

Chen*, S., Lin, F. & Hamm*, H. E. (2005). RACK1 binds to a signal transfer region of Gß? and inhibits PLCß2 activation. *Corresponding authors. J Biol Chem, 280(39), 33445-52. PMID: 16051595.

Lin, F., Sepich, D. S., Chen, S., Topczewski, J., Yin, C., Solnica-Krezel, L. & Hamm, H. (2005). Essential roles of G{alpha}12/13 signaling in distinct cell behaviors driving zebrafish convergence and extension gastrulation movements. J Cell Biol, 169(5), 777-87. PMID: 15928205.

Chen, S., Spiegelberg, B. D., Lin, F., Dell, E. J. & Hamm, H. E. (2004). Interaction of Gbetagamma with RACK1 and other WD40 repeat proteins. *Corresponding authors. J Mol Cell Cardiol, 37(2), 399-406. PMID: 15276010.

Chen, S., Dell, E. J., Lin, F., Sai, J. & Hamm*, H. E. (2004). RACK1 regulates specific functions of Gbetagamma. *Corresponding authors. J Biol Chem, 279(17), 17861-8. PMID: 14963031.

Sharpe, I. A., Thomas, L., Loughnan, M., Motin, L., Palant, E., Croker, D. E., Alewood, D., Chen, S., Graham, R. M., Alewood, P. F., Adams, D. J. & Lewis, R. J. (2003). Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA. J Biol Chem, 278(36), 34451-34457. PMID: 12824165.

Chen, S., Lin, F., Xu, M., Riek, R. P., Novotny, J. & Graham, R. M. (2002). Mutation of a single TMVI residue, Phe(282), in the beta(2)-adrenergic receptor results in structurally distinct activated receptor conformations. Biochemistry, 41(19), 6045-53. PMID: 11993999.

Chen, S., Lin, F., Xu, M. & Graham, R. M. (2002). Phe(303) in TMVI of the alpha(1B)-adrenergic receptor is a key residue coupling TM helical movements to G-protein activation. Biochemistry, 41(2), 588-96. PMID: 11781098.

Dell, E. J., Connor, J., Chen, S., Stebbins, E. G., Skiba, N. P., Mochly-Rosen, D. & Hamm, H. E. (2002). The ß? Subunit of Heterotrimeric G Proteins Interacts with RACK1 and Two Other WD Repeat Proteins. J Biol Chem, 277(51), 49888-49895. PMID: 12359736.

Lin, F., Owens, W. A., Chen, S., Scott, K., Michael, F., Stevens, M. E. & Graham, R. M. (2001). Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy. Cir Res, 89(4), 343-350. PMID: 11509451.

Chen, S., Xu, M., Lin, F. & Graham, R. M. (2000). Dominant-negative activity of the a1?-adrenergic receptor induced by a signal-inactivating point mutation. EMBO J, 19(16), 4265-4271. PMID: 10944109.

Chen, S., Xu, M., Lin, F., Riek, P. & Graham, R. M. (1999). Phe310 in TMVI of the a1B-adrenergic receptor is a key switch residue in activation and catecholamine ring aromatic bonding. J Biol Chem, 274(23), 16320-16330. PMID: 10347189.

Grayson, T. H., Ellis, J. M., Chen, S., Graham, R. M., Brown, R. D. & Hill, C. E. (1998). Immunohistochemical localization of a1?-adrenergic receptors in the rat iris. Cell and Tissue Res, 293(3), 435-444. PMID: 9716733.

Zhang, Y. Y., Tian, B., Chen, S. & Han, Q. D. (1997). Different susceptibility to desensitization of three a1-adrenoceptor subtypes induced by sustained norepinephrine stimulation. Acta Physiol Sinica, 49(1), 1-6.

Chen, S., Lin, F., Iismaa, S., Lee, K. N., Birckbichler, P. J. & Graham, R. M. (1996). a1-Adrenergic Receptor Signaling via Gh Is Subtype Specific and Independent of Its Transglutaminase Activity. J Biol Chem, 271(50), 32385-32391. PMID: 8943303.

Graham, R. M., Riek, P., Iismaa, S. & Chen, S. (1995). Adrenergic and dopamine receptors. In , D. Schlondorff , J. Bonventre (Eds.) In: Molecular Nephology. pp. 143-155.

Chen, S., Han, Q. D. (1995). Increased release of neuropeptide Y from platelets of spontaneously hypertensive rats. Acta Pharmacol Sinica, 16(2), 149-152.

Mu, L. X., Chen, S. & Han, Q. D. (1995). Platelet neuropeptide Y-like immunoreactive substances and their vasoconstrictor effects in rabbits. Chinese J Pharmal Toxicol, 9(1), 40-43.

Chen, S., Han, Q. D. (1995). Thrombin-induced neuropeptide Y secretion from rat platelets. Acta Pharmacol Sinica, 16(4), 1360-1365.

Chen, S., Han, Q. D. (1994). a1-Adrenergic receptor subtypes and ß-adrenergic receptors in isolated rat adult myocytes. Acta Beijing Med Univ, 26, 23.

Chen, S., Han, C. (1993). Regulation of cytoplasmic Ca2+ concentration. Progress in Physiological Science, 24, 10-13.