Journal of Proteomics & Bioinformatics
Open Access
ISSN: 0974-276X
+44 1223 790975
ISSN: 0974-276X
+44 1223 790975
Tzu-Ching Meng
Academia Sinica, Taiwan
Keynote: J Proteomics Bioinform
The Ras signaling cascade acts as a key driver in human colon cancer progression. Among the modules in this pathway, p38γ (MAPK12) and its specific protein tyrosine phosphatase PTPN3 (PTPH1) are critical regulators responsible for Ras oncogenic activity. However, the molecular basis for their interaction remains elusive. We showed both p38γ and PTPN3 being highly expressed in late-stage of human colon cancer tissues. Comprehensive structural information on the PTPN3-p38γ interaction is essential to understand their cooperative activities in Ras-dependent malignancies. Employing an advanced hybrid method integrating x-ray crystallography, small-angle x-ray scattering (SAXS), chemical cross-linking/mass spectrometry (CX-MS) and hydrogendeuterium exchange (HDX), we have obtained a unique architecture of the PTPN3-phosphorylated p38γ complex. Moreover, we showed that PTPN3 binds to unphosphorylated p38γ with micromolar affinity. Enzyme kinetics studies revealed that the presence of the PDZ binding motif of p38γ promotes the phosphatase activity of PTPN3. Using small-angle x-ray scattering, we found that PTPN3 adopts a predominantly compact shape in the absence of p38γ. After complex formation with unphosphorylated p38γ, we observed an extended conformation that was clearly different from that of the active state complex. Through chemical crosslinking coupled with mass spectrometry, we confirmed that the PDZ domain binds to the N-lobe region of unphosphorylated p38γ, thereby forming an end-to-end complex assembly. Overall, our results show that PTPN3 and unphosphorylated p38γ may form a resting-state complex, suggesting its unexpected function to promote colon cancer progression. Our structural data suggest the presence of the active-state complex (left) and the resting-state complex (right) between PTPN3 and p38γ The interaction of PDZ domain in PTPN3 and the ETPL motif in p38γ drives the complex formation. We show that the resting-state complex may promote oncogenic signaling involved in colon cancer progression. Recent Publications 1. Pan K T, Chen Y Y, Pu T H, Chao Y S, Yang C Y, Bomgarden R D, Rogers J C, Meng T C and Khoo K H (2014) Mass spectrometry based quantitative proteomics for dissecting multiplexed redox cysteine modifications in nitric oxideprotected cardiomyocyte under hypoxia. Antioxidants & Redox Signaling 20:1365-1381. 2. Chen K E, Lin S Y, Wu M J, Ho M R, Santhanam A, Chou C C, Meng T C and Wang A H J (2014) Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain modulated complex formation. Science Signaling doi: 10.1126/ scisignal.2005722. 3. Chen K E, Li M Y, Chou C C, Ho M R, Chen G C, Meng T C, Wang A H J (2015) Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases. Structure 23: 653-664. 4. Hsu MF , Pan K T, Chang F Y, Khoo K H, Urlaub H, Chang G D, Haj F G, and Meng T C (2016) S-Nitrosylation of endogenous protein tyrosine phosphatases in endothelial insulin signaling. Free Radical Biology and Medicine 99:199-213. 5. Hsu S F, Lee Y B, Lee Y C, Chung A L, Apaya M K, Shyur, L F, Cheng C F, Ho F M and Meng T C (2018) Dual specificity phosphatase DUSP6 promotes endothelial inflammation through inducible expression of ICAM-1. FEBS Journal doi: 10.1111/febs.14425.
Tzu-Ching Meng has completed his PhD from University of Nebraska Medical Center in 1999 and Postdoctoral studies from Cold Spring Harbor Laboratory in 2003. Since then, he has been working at Academia Sinica, the premier government-funded institution in Taiwan. He is now a Research Fellow with Professorship jointly appointed by National Taiwan University. He has published more than 40 papers in reputed journals and has been serving as an Advisory Board Member of competitive journals.