SHPS1 Protein: Research Advances in a Multifunctional Cell Surface Receptor

Discovery and Basic Structure of SHPS1 Protein

SHPS1 (SHP substrate 1), also known as SIRPα (Signal-regulatory protein α), is a widely expressed transmembrane glycoprotein in mammalian cells. First discovered in the late 1990s by multiple research teams almost simultaneously, it was named SHPS1 due to its role as a specific substrate for the tyrosine phosphatases SHP-1 and SHP-2. As research progressed, scientists gradually recognized its critical functions in immune regulation, intercellular communication, and various physiological and pathological processes.

From a molecular perspective, SHPS1 belongs to the immunoglobulin superfamily and exhibits unique structural characteristics. Its extracellular region contains three immunoglobulin-like domains: an N-terminal V-type domain and two C1-type domains. This structural feature enables interactions with multiple ligands, particularly the binding of its V-type domain to CD47, which has become a research hotspot. The transmembrane region of SHPS1 consists of a hydrophobic amino acid sequence, while the intracellular domain contains four tyrosine phosphorylation sites. When phosphorylated, these sites recruit SH2 domain-containing proteins, particularly the phosphatases SHP-1 and SHP-2, initiating downstream signaling. Notably, SHPS1 is highly conserved across species. In humans, the SHPS1 gene is located at chromosome 20p13 and is encoded by multiple exons. Post-translational glycosylation modifications result in a molecular weight of approximately 90–110 kDa, depending on the degree of glycosylation. These modifications not only affect protein stability but also regulate its ligand-binding capabilities.

Expression Distribution and Regulatory Mechanisms of SHPS1

SHPS1 expression exhibits significant tissue specificity. Studies show that it is most abundant in the immune system, particularly in myeloid cells such as macrophages, dendritic cells, and neutrophils. Additionally, neurons, epithelial cells, and endothelial cells also express SHPS1 at varying levels, suggesting its potential roles in immune responses and the nervous system.

At the molecular level, SHPS1 expression is finely regulated by multiple factors. Pro-inflammatory cytokines like IFN-γ and TNF-α can significantly upregulate SHPS1, while certain anti-inflammatory factors may suppress its expression. Epigenetic modifications, particularly DNA methylation in the promoter region, have also been shown to regulate SHPS1 expression levels. Furthermore, specific microRNAs, such as miR-340 and miR-342-3p, can negatively regulate SHPS1 expression by binding to the 3' untranslated region of its mRNA.

Interestingly, SHPS1 expression undergoes dynamic changes in various pathological conditions. For example, abnormal SHPS1 expression has been observed in multiple tumor tissues—some showing upregulation and others downregulation—likely depending on tumor type and microenvironment. In neurodegenerative diseases like Alzheimer's, SHPS1 expression patterns in the brain are significantly altered, suggesting its involvement in disease progression.

Biological Functions and Molecular Mechanisms of SHPS1

As a multifunctional cell surface receptor, SHPS1 regulates several critical biological processes. Its most well-known function is modulating macrophage phagocytic activity through interaction with CD47. This mechanism, termed the "don't-eat-me" signal, occurs when SHPS1 binds CD47, activating intracellular SHP-1/SHP-2 and transmitting inhibitory signals that prevent macrophages from engulfing healthy cells. Tumor cells often exploit this mechanism by overexpressing CD47 to evade immune surveillance.

Beyond immune regulation, SHPS1 is involved in cell migration, proliferation, and differentiation. In neurons, SHPS1 regulates synaptic plasticity and neurite outgrowth through ligand interactions. Studies show that SHPS1 deficiency leads to abnormal neuronal morphology and synaptic dysfunction. In vascular endothelial cells, SHPS1 participates in angiogenesis and barrier function, with dysregulated expression linked to various vascular diseases.

From a mechanistic perspective, SHPS1 transmits signals in two primary ways: phosphatase-dependent and phosphatase-independent. In the phosphatase-dependent pathway, phosphorylation of tyrosine residues in the SHPS1 intracellular domain recruits and activates SHP-1/SHP-2, modulating downstream signaling. In the phosphatase-independent pathway, SHPS1 may function by forming complexes with other membrane proteins or influencing cytoskeletal reorganization. These intricate signaling networks enable SHPS1 to regulate diverse cellular behaviors.

Role of SHPS1 in Disease and Therapeutic Potential

Growing evidence indicates that SHPS1 plays a significant role in the pathogenesis of various diseases. In oncology, the SHPS1-CD47 axis has emerged as a promising target for cancer immunotherapy. Preclinical studies demonstrate that disrupting this interaction enhances macrophage-mediated tumor cell phagocytosis and boosts anti-tumor immune responses. Several anti-CD47 antibodies and SHPS1 antagonists are now in clinical trials, showing great therapeutic potential.

In neurodegenerative diseases, abnormal SHPS1 expression is closely linked to disease progression. Alzheimer's patients exhibit altered SHPS1 expression patterns in the brain, potentially affecting microglial activation and Aβ clearance. In Parkinson's disease models, SHPS1 regulates the survival of dopaminergic neurons. These findings provide potential targets for novel neuroprotective strategies.

Additionally, SHPS1 plays important roles in cardiovascular diseases, autoimmune disorders, and infectious diseases. For example, in atherosclerosis, SHPS1 influences plaque stability by modulating macrophage function. In systemic lupus erythematosus and other autoimmune diseases, dysregulated SHPS1 signaling may contribute to loss of immune tolerance. Targeted therapeutic strategies against SHPS1 for these conditions are under active investigation.

Challenges and Future Directions in SHPS1 Research

Despite significant progress, SHPS1 research faces several challenges. A major hurdle is the functional heterogeneity of SHPS1 across different cell types and tissues—the same molecule may exert distinct roles in immune cells versus neurons, complicating systematic functional analysis. Moreover, the precise regulatory mechanisms of SHPS1 signaling, particularly its crosstalk with other pathways, remain incompletely understood.

Future research directions include:

• Developing more specific SHPS1 modulation tools, such as conditional knockout mice and isoform-selective regulators.
• Using high-resolution imaging to study SHPS1's dynamic distribution and interactions on cell membranes.
• Exploring SHPS1's roles in metabolic regulation and inter-organ communication.
• Translating SHPS1-based therapeutic strategies into clinical applications.

With advancements in single-cell sequencing, proteomics, and structural biology, scientists are poised to gain a more comprehensive understanding of SHPS1's biological significance. This multifunctional cell surface receptor will continue to offer rich scientific questions and therapeutic opportunities. In-depth research on SHPS1 will not only enhance our knowledge of cellular signaling but may also lead to breakthroughs in treating major diseases.

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