Abstract 873: The mechanisms of SHP2 activation in cancer and neurodevelopmental disorder
Authors: Liu Yonglan , Zhang Mingzhen , Zhang Wengang , Jang Hyunbum , Nussinov Ruth 
Published: April 2023

Abstract
The Src homology 2 domain-containing phosphatase 2 (SHP2) is a nonreceptor protein tyrosine phosphatase that regulates Ras/MAPK pathway, leading to cell proliferation. SHP2 mutations are commonly associated with human malignancies and neurodevelopmental disorders (NDDs). Somatic SHP2 mutations are associated with many types of cancer including sporadic juvenile myelomonocytic leukemia, acute myeloid leukemia, breast, gastric, lung, melanoma, and colorectal cancers, while heterozygous germline mutations are linked to NDDs such as Noonan and LEOPARD syndromes. Interestingly, different mutations at the same genomic loci of the gene result in different disease phenotypes, either cancer or NDDs. Patients with NDDs have a higher chance of developing cancer, suggesting a linkage between cancer and NDDs, and between their mutations. SHP2 consists of two SH2 domains (nSH2 and cSH2), a phosphatase (PTP) domain, and a flexible C-terminal tail. In autoinhibition, SHP2 is catalytically inactive, adopting a closed conformation in which the DE-loop of nSH2 blocks the catalytic site of PTP. The binding of nSH2 to the phosphotyrosine (pY)-motif relieve the autoinhibition via disruption of the nSH2-PTP interface. To depict mechanism of the mutation-associated activation of SHP2, extensive molecular dynamics simulations were performed for SHP2 protein with the mutations related to cancer and NDDs. The dynamics and conformational alterations of the wild type, cancer mutants (E76K, D61Y, D61V), and NDD mutants (E76D, D61G) of SHP2 were compared. Collective results showed that both cancer and NDD mutations weaken the nSH2-PTP interface, facilitating the SHP2 activation. Interestingly, cancer mutations induce stronger destruction at the nSH2-PTP interface than the NDD mutations. The PTP domain exhibits two pockets, orthosteric and allosteric pockets, at the interface with nSH2. In autoinhibition, the orthosteric pocket provides a binding site for D61 of nSH2, and the allosteric pocket accommodates E76 and A72 of nSH2. During the simulations, we observed that the mutations, E76K and E76D, reduce the interaction in the allosteric pocket, increasing the probability toward the open SHP2 conformation. This gradually weakens the interactions of D61 in the orthosteric pocket, promoting SH2 release and leading to SHP2 activation. The three mutations, D61Y, D61V, and D61G, directly disrupted the interaction in the orthosteric pocket, favoring the substrate binding. However, they do not optimize the nSH2 conformation for the pY binding and unlikely affect the interaction in the allosteric pocket. Our works explain the difference and similarity between the cancer and NDD mutations of SHP2 at the atomic level and provide deeper understanding of the mutation-induced activation of SHP2 for signal transduction through the Ras/MAPK pathway.
Citation Format: Yonglan Liu, Mingzhen Zhang, Wengang Zhang, Hyunbum Jang, Ruth Nussinov. The mechanisms of SHP2 activation in cancer and neurodevelopmental disorder [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 873.