Pharmacology

Songhai Chen, MD, PhD

Portrait

Associate Professor of Pharmacology
Associate Professor of Internal Medicine

Contact Information

Primary Office: 2-250 Bowen Science Building
Iowa City, IA 52242
Primary Office Phone: 319-384-4562

Lab: 2-240 Bowen Science Building
Iowa City, IA 52242
Phone: 319-384-4563

Email: songhai-chen@uiowa.edu

Education

MD, Fujian Medical University, Fuzhou, P.R. China
MS, Beijing Medical University, Beijing, P.R. China (now Health Science Center, Peking University)
PhD, School of Medicine, University of New South Wales, Sydney Australia

Resident, Zhangzhou First Hospital, Dept of Internal Medicine, Fujian Province, China
Research Assistant Professor, Institute of Vascular Medicine, Beijing Medical University, Beijing, China
Visiting Scientist, Dept of Biology & Biochemistry, Massachusetts Institute of Technology, MA
Senior Research Fellow (NHMRC-funded), Biochemistry and Molecular Pharmacology, University of New South Wales, Sydney, Australia
Research Fellow, Pharmacology, Vanderbilt University School of Medicine, TN

Education/Training Program Affiliations

Biosciences Graduate Program
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 βγ subunits orchestrate the formation of specific signaling complexes to promote directional cell migration. Particularly, we are interested in understanding how Gβγ 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 Gβγ 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 Gβγ stimulates key signaling molecules such as PI3Kγ to promote cell migration. However, Gβγ 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 Gβγ- interacting proteins opens a new era in understanding the function and regulation of Gβγ signaling. These proteins are predicted to form a similar β-propeller structure with multiple surfaces as Gβ (Figure). Therefore, like Gβγ, they have the potential to assemble wide array of proteins to promote or inhibit Gβγ-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 Gβγ, and the role of these proteins in regulating Gβγ-mediated cell migration. RACK1 is found to bind to a unique side-surface of Gβγ through a novel protein-protein interaction, WD40-WD40 repeat interaction. Binding of RACK1 to Gβγ selectively abrogates the activation of key signaling molecules, PI3K and PLCβ, 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/ Gβγ interaction in tumor metastasis, since chemokine receptors, which are frequently found to be overexpressed in tumor, also promote tumor cell migration through Gβγ; To delineate the function of other Gβγ-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.

All Publications

Xi H, Ye D, Behra M, Burgess S, Chen S, Lin F.  Gβ1 controls collective cell migration by regulating the protrusive activity of leader cells in the posterior lateral line primordium.  Dev Biol.  2013 November. 
[Link]

Runne C, Chen S.  PLEKHG2 Promotes Heterotrimeric G Protein βγ-Stimulated Lymphocyte Migration via Rac and Cdc42 Activation and Actin Polymerization.  Mol Cell Biol.  2013 November. 33(21):4294-4307.
[Link]

Sun Z, Smrcka A, Chen S.  WDR26 functions as a scaffolding protein to promote Gβγ-mediated phospholipase C β2 (PLCβ2) activation in leukocytes.  J Biol Chem.  2013 June 7. 288(23):16715-16725.
[Link]

Runne C, Chen S.  WD40-repeat proteins control the flow of Gβγ signaling for directional cell migration.  Cell Adh Migr.  2013 March. 7(2):214-218.
[Link]

Sun Z, Runne C, Lin F, Chen S.  The Gβ3 splice variant associated with the C825T gene polymorphism is an unstable and functionally inactive protein.  Cell Signal.  2012 December. 24(12):2349-2359.
[Link]

Chen S.  WDR26 regulates the Gbetagamma-stimulated PI3K/AKT signaling axis for breast cancer cell growth and migration.  Gordon conference on Phosphorylation & G-protein Mediated Signaling Networks, University of New England.  2012 June 10. 

Xu H, Kardash E, Chen S, Raz E, Lin F.  Gβγ signaling controls the polarization of zebrafish primordial germ cells by regulating Rac activity.  Development.  2012 January. 139(1):57-62.
[Link]

Chen S.  Identification of WDR26 as a novel Gbetagamma-binding protein that promotes leukocyte migration.  Keystone Symposia on Chemokines and Leukocyte Trafficking in Homeostasis and Inflammation, Colorado.  2012 January. 

Sun Z, Tang X, Lin F, Chen S.  The WD40-repeat protein WDR26 binds Gbg and promotes Gbg-dependent signal transduction and leukocyte migration.  J Biol Chem.  2011 December 23. 286(51):43902-43912.
[Link]

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

Tang X, Sun Z, Runne C, Madsen J, Domann F, Henry M, Lin F, Chen S.  A critical role of Gbetagamma in tumorigenesis and metastasis of breast cancer.  J Biol Chem.  2011 April 15. 286(15):13244-13254.
[Link]

Chen S.  Activation of PLEKHG2 RhoGEF by selective G isoforms released from multiple classes of G proteins.  EB meeting, Washington, DC.  2011 April. 

Chen S.  Spatiotemporal regulation of Gbetagamma signaling and function by a novel Gbetagamma-interacting protein, WDR26.  EB Meeting, WAshington, DC.  2011 April. 

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

Chen S.  A critical role of Gbetagamma in breast tumor growth and metastasis.  AACR Annual Meeting, Washington, DC .  2010 April 17. 

Chen S.  Identification of WDR26 as a novel interacting protein of Gbetagamma that mediates leukocyte migration.  Gordon Conference on Phosphorylation and G protein Mediated Signaling Network, University of New England, Biddeford, ME.  2009 June 7. 

Lin F, Chen S, Sepich D, Panizzi J, Clendenon S, Marrs J, Hamm H, Solnica-Krezel L.  Galpha12/13 regulate epiboly by inhibiting E-cadherin activity and modulating the actin cytoskeleton.  J Cell Biol.  2009 March 23. 184(6):909-921.
[Link]

Chen S.  Regulation of G protein signaling in leukocyte migration.  Gordon Conference on Gradient Sensing & Directed Cell Migration, Galveston, TX, Mar29-Apr 3,.  2009. 

Chen S.  Targeting Gbetagamma to inhibit tumorigenesis and metastasis of breast.  Midwest Breast Cancer Research Symposium, Iowa City, IA, p39.  2009. 

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

Chen S.  RACK1 regulates directional cell migration by acting on Gβγ at the interface with its effectors PLCbeta and PI3Kgamma.  The Keystone Symposium on Chemokines and Chemokine Receptors. p121.  2008. 

Chen S, Hamm H.  DEP domains: more than just membrane anchors.  Dev Cell.  2006. 11:436-438.

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

Chen S, Lin F, Hamm H.  RACK1 binds to a signal transfer region of G betagamma and inhibits phospholipase C beta2 activation.  J Biol Chem.  2005 September 30. 280(39):33445-52.
[Link]

Lin F, Sepich D, Chen S, Topczewski J, Yin C, Solnica-Krezel L, Hamm H.  Essential roles of Galpha 12/13 signaling in distinct cell behaviors driving zebrafish convergence and extension gastrulation movements.  J Cell Biol.  2005 June 6. 169(5):777-87.
[Link]

Chen S, Dell E, Lin F, Sai J, Hamm H.  RACK1 regulates specific functions of Gbetagamma.  J Biol Chem.  2004 April 23. 279(17):17861-8.
[Link]

Chen S, Spiegelberg B, Lin F, Dell E, Hamm H.  Interaction of Gbetagamma with RACK1 and other WD40 repeat proteins.  J Mol Cell Cardiol.  2004. 37:399-406.

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

Chen S, Lin F, Xu M, Riek R, Novotny J, Graham R.  Mutation of a single TMVI residue, Phe(282), in the beta(2)-adrenergic receptor results in structurally distinct activated receptor conformations.  Biochemistry.  2002 May 14. 41(19):6045-53.
[Link]

Chen S, Lin F, Xu M, Graham R.  Phe(303) in TMVI of the alpha(1B)-adrenergic receptor is a key residue coupling TM helical movements to G-protein activation.  Biochemistry.  2002 January 15. 41(2):588-96.
[Link]

Dell E, Connor J, Chen S, Stebbins E, Skiba N, Mochly-Rosen D, Hamm H.  The βγ Subunit of Heterotrimeric G Proteins Interacts with RACK1 and Two Other WD Repeat Proteins.  J Biol Chem.  2002. 277:49888-49895.

Lin F, Owens W, Chen S, Scott K, Michael F, Stevens M, Graham R.  Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy.  Cir Res.  2001 August 17. 89(4):343-350.
[Link]

Chen S, Xu M, Lin F, Graham R.  Dominant negative activity of the α1Β-adrenergic receptor induced by a signal-inactivating point mutation.  EMBO J.  2000. 19:4265-4271.

Chen S, Xu M, Lin F, Riek P, Graham R.  Phe310 in TMVI of the α1B-adrenergic receptor is a key switch residue in activation and catecholamine ring aromatic bonding.  J Biol Chem.  1999. 274:16320-16330.

Grayson T, Ellis J, Chen S, Graham R, Brown R, Hill C.  Immunohistochemical localization of α1Β-adrenergic receptors in the rat iris.  Cell and Tissue Res.  1998. 293(3):435-444.

Zhang Y, Tian B, Chen S, Han Q.  Different susceptibility to desensitization of three α1-adrenoceptor subtypes induced by sustained norepinephrine stimulation.  Acta Physiol Sinica.  1997. 49(1):1-6.

Chen S, Lin F, Iismaa S, Lee K, Birckbichler P, Graham R.  α1-Adrenergic Receptor Signaling via Gh Is Subtype Specific and Independent of Its Transglutaminase Activity.  J Biol Chem.  1996 December 13. 271(50):32385-32391.
[Link]

Graham R, Riek P, Iismaa S, Chen S.  Adrenergic and dopamine receptors. .  In: Molecular Nephology.  1995. 

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

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

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

Chen S, Han Q.  α1-Adrenergic receptor subtypes and ß-adrenergic receptors in isolated rat adult myocytes.  Acta Beijing Med Univ.  1994. 26:23.

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

Sun Z, Ye Y, Grobe J, Chen S.  Disruption of the Gbega3 gene does not affect blood pressure or metabolism in mice. 

Ke W, Mesch K, Ye D, Xu H, Chen S, Lin F.  Identification of G1 as a key G isoform that controls neutrophil migration during wound healing in zebrafish.  Development. 

Ye Y, Tang X, Sun Z, Chen S.  WDR26 scaffolds the interaction of PI3K and AKT with G to promote breast tumor cell growth, migration and invasion.  Cancer Research. 

Date Last Modified: 07/02/2014 - 13:12:29