Faculty Summaries
Jinhua Wu, PhD
Jinhua Wu, PhD
Assistant Professor
Office Phone: 215-728-2867
Fax: 215-728-3616
Office: W410
Structural Studies of RIAM-Mediated Integrin Activation

Integrins regulate signaling events that control cell adhesion, migration, and proliferation. Misregulation of integrin signaling has been linked to tumorigenesis and metastasis of various cancers, and many other life-threatening diseases. Activation of integrins is induced by either extracellular matrix association via an outside-in pathway or cytosolic signaling initiated by transmembrane receptors via an inside-out pathway. Although an-tagonistic agents targeting the extracellular moiety of integrins have entered clinical trials for cancer treatment, most are ineffective due to unexpected and paradoxical integrin-activating effects that are poorly understood. Integrin activities may also be suppressed by blocking the specific interactions of intracellular elements in the inside-out signaling, in which Rap1-GTP-interacting adaptor molecule (RIAM) mediates the signaling transduc-tion from activated Rap1 to talin, leading to integrin activation. We are poised to thoroughly elucidate the specific interactions mediating the Rap1-RIAM-talin-integrin signal-ing pathway and the regulatory mechanisms of talin by homodimerization and RIAM association. These aims will be accomplished through a combination of X-ray crystallographic studies, in vitro biochemical assays, and in-cell functional studies. Our results will provide detailed structural mechanisms of the signaling events that mediate the inside-out integrin activation to facilitate the efforts on developing novel therapeutic agents. 

Description of research projects
Selected Publications
  1. Yang J, Zhu L, Zhang H, Hirbawi J, Fukuda K, Dwivedi P, Liu J, Byzova T, Plow EF, Wu J**, Qin J**. Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion. Nat Comm Epub 2014 Dec 18.PubMed
  2. Chang YC, Zhang H, Brennan ML, Franco-Barraza J, Patel T, Cukierman E, Wu J. Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling. Structure 2014 22(12):1810-20 PubMed
  3. Zhang H, Chang YC, Brennan ML, Wu J. The structure of Rap1 in complex with RIAM reveals specificity determinants and recruitment mechanism. J Mol Cell Biol 2014 6(2):128-39 PubMed
  4. Anastassiadis T, Duong-Ly KC, Deacon SW, Lafontant A, Ma H, Devarajan K, Dunbrack RL Jr, Wu J, Peterson JR. A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor. J Biol Chem. 2013 Sep 27;288(39):28068-77. doi: 10.1074/jbc.M113.505032. Epub 2013 Aug 9.PubMed
  5. Chang YC, Zhang H, Brennan ML, Wu J. Crystal structure of Lamellipodin implicates diverse functions in actin polymerization and Ras signaling. Protein Cell. 2013 Mar;4(3):211-9. doi: 10.1007/s13238-013-2082-5. Epub 2013 Mar 13.PubMed
  6. Wynne JP*, Wu J*, Su W, Mor A, Patsoukis N, Boussiotis VA, Hubbard SR, Philips MR. Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector. J Cell Biol. 2012 Oct 15;199(2):317-30. doi: 10.1083/jcb.201201157. Epub 2012 Oct 8. *Equal contribution. PubMed
  7. Ungureanu D, Wu J, Pekkala T, Niranjan Y, Young C, Jensen ON, Xu CF, Neubert TA, Skoda RC, Hubbard SR, Silvennoinen O. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol. 2011 Aug 14. [Epub ahead of print] PubMed
  8. Depetris RS*, Wu J*, Hubbard, S.R. Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Nat Struct Mol Biol. 2009;16,833-9. *Equal contribution. PubMed
  9. Wu J*, Li W*, Craddock BP, Foreman KW, Mulvihill MJ, Ji QS, Miller WT, Hubbard SR. Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor. EMBO J. 2008;27,1985-94. *Equal contribution. PubMed
  10. Wu J, Tseng Y, Xu C, Neubert TA, White MF, and Hubbard SR. Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol. 2008;15,251-8. PubMed
All publications