GM-CSF Receptor: Roles, Signaling, and Impact on Cell Growth

Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates immune responses by influencing the survival, proliferation, and function of myeloid cells. Its effects are mediated through the GM-CSF receptor (GM-CSFR), a cell surface receptor that activates signaling pathways critical for hematopoiesis and inflammation.

Dysregulation of GM-CSFR signaling has been linked to leukemia, pulmonary alveolar proteinosis, and inflammatory disorders. Understanding its structure, expression, and signaling mechanisms provides insight into immune function and potential therapeutic targets.

Structural Composition

The GM-CSF receptor (GM-CSFR) is a heterodimeric complex composed of an α subunit (CSF2RA) and a β subunit (CSF2RB), each with distinct roles. The α subunit binds the ligand, while the β subunit drives intracellular signaling. Together, they form a high-affinity receptor complex essential for proper signaling. Even minor structural alterations can disrupt function.

CSF2RA encodes the α subunit, a type I transmembrane protein with an extracellular cytokine receptor homology module containing two fibronectin type III domains for ligand binding. CSF2RB encodes the β subunit, which is shared with receptors for interleukin-3 (IL-3) and interleukin-5 (IL-5), allowing functional redundancy. The β subunit facilitates receptor dimerization and contains tyrosine-rich intracellular domains that serve as docking sites for signaling molecules.

Upon ligand binding, the α subunit undergoes a conformational change, enabling interaction with the β subunit and receptor dimerization. This structural rearrangement recruits intracellular signaling proteins that recognize phosphotyrosine motifs on the β subunit, influencing cellular responses such as proliferation and survival. Mutations affecting these domains can lead to dysfunctional signaling and disease.

Expression Patterns

GM-CSFR expression is tightly controlled, varying by cell type and developmental stage to align with hematopoietic and myeloid cell needs. The α subunit (CSF2RA) is primarily expressed in myeloid cells, including monocytes, macrophages, neutrophils, and eosinophils, while the β subunit (CSF2RB) has broader distribution due to its shared role in IL-3 and IL-5 signaling. This selective expression enables precise GM-CSF signaling and crosstalk with other cytokine pathways.

Expression is modulated by cytokine availability, differentiation status, and inflammatory stimuli. Myeloid progenitors in the bone marrow have low GM-CSFR levels, which increase as they mature into monocytes and granulocytes. Tissue-resident macrophages, such as alveolar macrophages, maintain high GM-CSFR expression due to their reliance on GM-CSF for homeostasis. In contrast, peripheral blood monocytes adjust receptor levels in response to environmental cues like infection or tissue damage.

Regulation occurs at transcriptional and post-transcriptional levels. Transcription factors such as PU.1 and C/EBPβ promote CSF2RA expression, while microRNAs like miR-155 influence mRNA stability. Post-translational mechanisms, including receptor internalization and degradation, prevent excessive signaling. In diseases like leukemia, receptor overexpression enhances GM-CSF-driven proliferation, while in pulmonary alveolar proteinosis, defective signaling impairs macrophage function.

Signal Transduction Mechanisms

GM-CSF binding to its receptor triggers intracellular signaling that regulates proliferation, differentiation, and survival. The receptor itself lacks kinase activity, relying on Janus kinase 2 (JAK2) to propagate the signal. JAK2 associates with the β subunit’s intracellular domain and, upon receptor dimerization, undergoes autophosphorylation, creating docking sites for signaling proteins.

A key downstream pathway is the signal transducer and activator of transcription (STAT) pathway, particularly STAT5. Phosphorylated STAT5 dimerizes and translocates to the nucleus, regulating genes involved in cell cycle progression and survival, including BCL-XL and MYC. The mitogen-activated protein kinase (MAPK) pathway is also activated through the adaptor protein Shc, initiating the Ras-Raf-MEK-ERK cascade, which promotes proliferation. Additionally, the phosphoinositide 3-kinase (PI3K)-Akt pathway enhances survival by inhibiting pro-apoptotic factors such as BAD.

Signaling is tightly regulated to prevent prolonged activation. Suppressor of cytokine signaling (SOCS) proteins, particularly SOCS1 and SOCS3, bind phosphotyrosine residues on the β subunit or JAK2, leading to ubiquitin-mediated degradation of signaling complexes. Protein tyrosine phosphatases like SHP-1 dephosphorylate key residues, restoring the receptor to an inactive state. Dysregulation of these controls can contribute to unchecked cell proliferation or impaired apoptosis.

Genetic Variations

Variations in CSF2RA and CSF2RB affect receptor function and cellular responses. Single nucleotide polymorphisms (SNPs) identified in genome-wide association studies have been linked to differences in hematopoietic behavior and disease susceptibility. Missense mutations in CSF2RA can disrupt ligand binding, while alterations in CSF2RB may impair signal transduction by interfering with tyrosine phosphorylation sites.

Loss-of-function mutations in CSF2RA are associated with congenital pulmonary alveolar proteinosis, a rare lung disease caused by defective receptor assembly or premature truncation, leading to impaired surfactant clearance. Conversely, gain-of-function mutations in CSF2RB are linked to hematologic malignancies, where hyperactive signaling drives excessive myeloid proliferation. In some leukemias, tandem duplications or point mutations in the β subunit enhance JAK2 activation, prolonging proliferative signals and contributing to uncontrolled cell growth.

Functional Roles in Cell Growth and Differentiation

GM-CSFR plays a central role in regulating myeloid cell proliferation and differentiation. Its activation balances self-renewal and maturation, ensuring progenitor cells expand or progress toward differentiation based on physiological demands. This enables rapid myeloid cell production in response to infection or tissue injury. GM-CSFR signaling enhances progenitor survival by upregulating anti-apoptotic proteins and promoting cell cycle progression through STAT5-mediated activation of MYC and cyclin D1.

Beyond proliferation, GM-CSFR influences lineage commitment, guiding multipotent progenitors toward monocyte and granulocyte fates. The intensity and duration of signaling shape differentiation, with strong activation favoring monocyte development and weaker signaling supporting granulocytic pathways. Transcription factors such as PU.1 and C/EBPβ mediate lineage-specific gene expression. Experimental models show that GM-CSFR deletion impairs monocyte and macrophage development, highlighting its necessity in myeloid differentiation.

Dysregulated GM-CSFR activity is implicated in leukemogenesis, where abnormal signaling skews differentiation and promotes uncontrolled proliferation. Its role in maintaining balanced hematopoiesis underscores its importance in preventing pathological deviations in cell growth.