SHP2 is a protein found throughout the body, playing a fundamental part in how cells communicate and grow. This protein helps manage various processes inside our cells, working behind the scenes to keep things functioning properly.
Understanding SHP2
SHP2 is classified as a protein tyrosine phosphatase (PTP), meaning it removes phosphate groups from specific amino acids called tyrosines on other proteins. This action is like flipping a switch, turning off or modulating signals within the cell. SHP2 is widely distributed in various tissues, with higher levels observed in the heart, brain, and skeletal muscle.
This protein is an important player in regulating cellular growth, survival, differentiation, and migration. It acts downstream of various signals initiated by growth factors, hormones, and cytokines, helping to transmit these signals from the cell surface to the nucleus. SHP2’s ability to dephosphorylate proteins makes it a molecular switch that influences pathways like the Ras-Raf-MAP kinase, JAK/STAT, and PI3K/Akt pathways.
SHP2 has a modular structure, including two Src homology 2 (SH2) domains at its N-terminus and a catalytic PTP domain. In its inactive state, one of the SH2 domains blocks the catalytic site, preventing its activity. When SHP2 binds to specific phosphotyrosine residues on target proteins, a change in its shape occurs, opening up the catalytic site and activating the enzyme.
SHP2’s Role in Disease
When SHP2 malfunctions, often due to genetic mutations, it can contribute to a range of human diseases. Mutations in the gene encoding SHP2, called PTPN11, are linked to developmental disorders and various cancers. These mutations can either enhance or reduce SHP2’s activity, leading to different disease outcomes.
One notable developmental disorder associated with PTPN11 mutations is Noonan syndrome (NS). In about half of NS cases, activating mutations in PTPN11 lead to a hyperactive SHP2 protein. This overactivity can disrupt the Ras-MAPK pathway, which is involved in cell growth and development, contributing to features such as distinctive facial characteristics, short stature, and congenital heart defects. For example, studies in mouse models of NS have shown that mutated SHP2 can inhibit insulin-like growth factor 1 (IGF-1) release, contributing to growth retardation.
SHP2 also plays a complex role in cancer, sometimes acting as an oncogene that promotes tumor growth and other times as a tumor suppressor. Activating mutations in PTPN11 or increased SHP2 activity are frequently found in various blood cancers and solid tumors. In these cases, SHP2 can drive uncontrolled cell growth and survival.
For instance, SHP2 is involved in the progression of specific cancers such as leukemia, lung adenocarcinoma, colon cancer, breast cancer, glioblastoma, and melanoma. It can promote tumor cell proliferation, invasion, and even drug resistance. Some research indicates that SHP2 can also influence the tumor’s surrounding environment by affecting immune cell function, further supporting tumor growth.
Targeting SHP2 in Medicine
Given its involvement in various diseases, SHP2 has emerged as a promising target for drug development. The aim is to create therapies that can specifically inhibit or modulate SHP2 activity to treat conditions like cancer and developmental disorders.
Researchers have been exploring different strategies to develop SHP2 inhibitors. While traditional inhibitors targeting the enzyme’s catalytic site faced challenges with cell permeability and bioavailability, the discovery of allosteric inhibitors has opened new avenues. These allosteric inhibitors bind to a different site on SHP2, stabilizing its inactive form and thereby preventing its overactivity.
Several SHP2 allosteric inhibitors are currently undergoing clinical trials for solid tumors. For example, the allosteric inhibitor SHP099 has demonstrated the ability to suppress cancer cell proliferation by inhibiting the RAS-ERK signaling pathway, showing anti-tumor effects in mouse models. These inhibitors are being explored both as single agents and in combination with other anti-cancer drugs, particularly to overcome drug resistance in tumors with specific mutations.