SHP-1, also known as protein tyrosine phosphatase non-receptor type 6 (PTPN6), is an intracellular protein phosphatase. It belongs to the non-receptor class 2 subfamily. SHP-1 regulates various cellular processes, including cell growth, differentiation, and the mitotic cycle.
SHP-1’s Fundamental Role in Cellular Communication
SHP-1 functions as a phosphatase, an enzyme that removes phosphate groups from other proteins within cells. This process, called dephosphorylation, acts like a “switch” to turn off or regulate signals, influencing how cells communicate, grow, and survive.
SHP-1 specifically targets and dephosphorylates phosphotyrosine residues in proteins, counteracting protein tyrosine kinases which add phosphate groups. This dynamic balance between phosphorylation and dephosphorylation is necessary for maintaining specific signaling events within cells. SHP-1 contains two Src homology 2 (SH2) domains at its N-terminal, which bind to phosphorylated tyrosine residues, and a catalytic domain at its C-terminal that performs the phosphatase activity. In its inactive state, SHP-1 adopts an auto-inhibited conformation where its SH2 domains block the catalytic site, released upon binding to phosphorylated peptides.
SHP-1’s Impact on Immune System Function
SHP-1 is broadly found in hematopoietic cells, which are cells involved in blood formation. It acts as a negative regulator of signaling in both innate and adaptive immune cells. This enzyme regulates various immune cell functions, including antigen presentation, phagocytosis, and the differentiation of myeloid-derived suppressor cells. It exerts its inhibitory signaling by binding to phosphorylated immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on various immunoreceptors.
In T cells, SHP-1 is recruited to the cell membrane upon phosphorylation of inhibitory immune receptor domains. There, it dephosphorylates and inactivates key mediators of T cell activation, contributing to immunosuppression. For instance, SHP-1 limits antigen-specific T cell activation by dephosphorylating the T-cell receptor (TCR) zeta chain or downstream adapter proteins like Lck and ZAP70. SHP-1 also restricts the development of memory phenotype T cells and regulates interleukin-4 (IL-4) signaling, preventing sustained activation of STAT6, which can lead to enhanced Th2 skewing and elevated serum IgE levels.
SHP-1 also impacts signaling pathways in myeloid cells, including neutrophils, dendritic cells, macrophages, and mast cells. It helps dampen activating signals initiated by ITAM-containing proteins, such as integrins and Fc receptors, by being recruited by ITIM-containing proteins. In macrophages, SHP-1 binds to phosphorylated peptide sequences from SIRPĪ± and transmits an anti-phagocytic signal, meaning its loss can increase the phagocytosis of tumor cells.
SHP-1 and Its Link to Disease
Dysregulation of SHP-1 function can lead to abnormal cell growth and contribute to various diseases, including cancer and autoimmune disorders. In many cancers, SHP-1 often acts as a tumor suppressor by attenuating signaling pathways that control cell proliferation, survival, migration, and invasion. For example, SHP-1 negatively regulates the oncogenic STAT3 signaling pathway by directly dephosphorylating JAK and STAT3, which can curb tumor development and progression.
However, SHP-1’s role in cancer is complex and varies depending on the cancer type. In some hematological malignancies, such as leukemia and lymphoma, SHP-1 expression is often reduced or absent due to hypermethylation of its gene promoter. Conversely, SHP-1 can be normally or over-expressed in some non-lymphocytic cell lines, including prostate, ovarian, and breast cancer cells, and in some contexts, it may even promote tumor growth by influencing the tumor microenvironment.
In autoimmune diseases, SHP-1 deficiency often leads to widespread inflammation and autoimmune symptoms, as seen in “motheaten” mice with mutations in the SHP-1 gene. These mice exhibit hyperactivation of multiple immune cell types, leading to conditions like inflammatory skin disease. SHP-1 is considered a regulator in maintaining immune tolerance, and its dysfunction can result in uncontrolled immune responses, contributing to conditions such as allergic asthma, rheumatoid arthritis, and multiple sclerosis. The inflammatory phenotype in SHP-1 deficient mice is often driven by microbes activating TLR signaling pathways, leading to IL-1 production.
Exploring SHP-1 for Therapeutic Development
Given its diverse roles in cellular signaling and disease, SHP-1 is being explored as a potential target for therapeutic development. Scientists are investigating ways to modulate SHP-1 activity to treat various conditions. For instance, enhancing SHP-1 activity through compounds known as SHP-1 agonists holds promise for treating autoimmune diseases by dampening excessive inflammation and modulating immune cell activation.
Conversely, in some cancers, inhibiting SHP-1 activity is being explored as a strategy to unleash both innate and adaptive immunity against tumor cells, promoting anti-tumor responses. This approach could potentially enhance the efficacy of immunotherapies. The development of drugs that specifically activate or inhibit SHP-1 represents a promising area for future medical interventions.