Growth Factor Families: Structure, Receptors, and Signaling

ERBB Family Overview

The ERBB (HER) receptor family comprises four members: EGFR/ERBB1/HER1, HER2/ERBB2, HER3/ERBB3, and HER4/ERBB4. All are transmembrane glycoproteins with an extracellular ligand-binding domain, a transmembrane helix, an intracellular juxtamembrane region, and an intracellular kinase domain (except HER3, which has an impaired kinase). They signal primarily as dimers — all homo- and heterodimer combinations are possible, with HER2 being the preferred dimerization partner and HER2/HER3 the most potently signaling pair.

EGF Structure: EGF is a 53-amino acid protein containing three disulfide bonds forming three loops. The EGF domain is found across many proteins (NRG, TGF-α, HB-EGF). It binds domain II and IV of EGFR, inducing an "extended" EGFR conformation that exposes a dimerization arm on domain II.

Platelet-Derived Growth Factor

PDGF was originally isolated from platelets as a major serum mitogen for fibroblasts and smooth muscle cells. The PDGF family now comprises five dimeric ligands (PDGF-AA, -AB, -BB, -CC, -DD) formed from four polypeptide chains (PDGF-A, -B, -C, -D). They signal through two RTKs: PDGFRα and PDGFRβ.

• PDGF-BB: Most potent; activates both PDGFRα and PDGFRβ; major roles in pericyte recruitment, wound healing, and hematopoiesis. Overproduced in many tumors, driving cancer-associated fibroblast proliferation and tumor stroma formation.
• PDGFRα mutations: Gain-of-function PDGFRα mutations (D842V, V561D) are oncogenic drivers in gastrointestinal stromal tumors (GIST) — treated with imatinib, avapritinib. PDGFRα amplification occurs in glioblastoma.
• Dermatofibrosarcoma protuberans (DFSP): Contains the COL1A1-PDGFB fusion translocation, creating an autocrine PDGF-BB loop activating PDGFRβ. Imatinib is highly effective therapy.

Fibroblast Growth Factor Family

The FGF family comprises 22 members (FGF1–23, excluding FGF15 which is the rodent ortholog of FGF19) signaling through four RTKs — FGFR1–4 — each with multiple splice isoforms. FGF signaling requires heparan sulfate proteoglycans (HSPGs) as obligatory co-receptors, which stabilize the FGF-FGFR ternary complex. This HSPG requirement makes FGF signaling sensitive to the extracellular matrix environment.

FGFR Alterations in Cancer: FGFR alterations are among the most common RTK alterations across all cancers. FGFR2 gene fusions (FGFR2-BICC1, FGFR2-AHCYL1) are found in ~15% of intrahepatic cholangiocarcinoma (iCCA) — targeted by FGFR inhibitors such as pemigatinib and futibatinib. FGFR3 mutations/fusions drive ~20% of bladder cancer — targeted by erdafitinib (FDA-approved).

Vascular Endothelial Growth Factor

The VEGF family comprises VEGF-A, -B, -C, -D, and PlGF (placental growth factor), signaling through three RTKs: VEGFR1 (FLT1), VEGFR2 (KDR/FLK1), and VEGFR3 (FLT4), plus neuropilin co-receptors (NRP1, NRP2). VEGF-A is the primary driver of angiogenesis; VEGF-C and -D activate VEGFR3 to drive lymphangiogenesis.

• VEGF-A isoforms: Alternative splicing produces isoforms of different lengths — VEGF121 (freely diffusible), VEGF165 (predominant; partially matrix-bound), VEGF189/206 (strongly matrix-bound). The ratio of pro-angiogenic to anti-angiogenic VEGF splice isoforms (VEGF165 vs VEGF165b) is regulated by SRSF1 splicing factor and is altered in cancer.
• HIF-1α regulation: Under hypoxia, HIF-1α binds the hypoxia-response element (HRE) in the VEGF-A promoter, driving transcription. VHL tumor suppressor ubiquitinates HIF-α for proteasomal degradation under normoxia; loss of VHL (in clear cell RCC) causes constitutive HIF/VEGF activation.
• Bevacizumab: Anti-VEGF-A monoclonal antibody (Genentech/Roche) — first approved anti-angiogenic therapy (2004). Approved in colorectal, lung, ovarian, renal, glioblastoma cancers. Bevacizumab + chemotherapy improves PFS and OS in multiple settings.
• VEGFR TKIs: Sunitinib, sorafenib, pazopanib, cabozantinib — multi-kinase inhibitors including VEGFR2 — are first-line therapy in metastatic RCC and HCC.
• Ranibizumab / aflibercept: In ophthalmology, anti-VEGF agents treat neovascular age-related macular degeneration (nAMD) and diabetic macular edema by blocking pathological choroidal angiogenesis.

Insulin-Like Growth Factor

The IGF axis comprises two ligands (IGF-1, IGF-2), two receptors (IGF-1R, IGF-2R), six high-affinity IGF-binding proteins (IGFBP1–6), and the insulin receptor (IR) — which forms hybrid receptors with IGF-1R in cancer cells. IGF-1 is primarily liver-derived (endocrine) in response to GH, but is also produced locally in autocrine/paracrine fashion in many tissues.

• IGF-1R signaling: IGF-1R activates IRS-1/IRS-2 adapter proteins, strongly engaging PI3K/AKT/mTORC1 — a major survival and growth pathway. It also activates RAS/MAPK. IGF-1R overexpression is common in breast, colon, and lung cancers.
• IGF-2 imprinting and Beckwith-Wiedemann: IGF-2 is normally expressed from the paternal allele (maternal allele silenced by imprinting). Loss of imprinting (biallelic IGF-2 expression) occurs in ~10% of colorectal cancers and is the mechanism of IGF-2 overexpression in Wilms tumor and Beckwith-Wiedemann syndrome (BWS).
• IGFBPs: The six IGFBPs bind IGF-1 and IGF-2 with affinities exceeding that of IGF-1R, sequestering ligand and modulating bioavailability. IGFBP-3, the most abundant, is an anti-tumor protein — promoting apoptosis via IGF-independent, nuclear mechanisms. IGFBP-3 is downregulated in many cancers.
• Anti-IGF-1R therapies: Multiple anti-IGF-1R antibodies (cixutumumab, figitumumab, ganitumab) and IGF-1R TKIs failed in unselected cancer populations. Ewing sarcoma — driven by EWS-FLI1 which upregulates IGF-1 autocrine signaling — showed occasional responses. Linsitinib (IGF-1R/IR TKI) showed modest activity in adrenocortical carcinoma.

Transforming Growth Factor-β: The Dual-Role Cytokine

The TGF-β superfamily is the largest growth factor family, with over 30 members including TGF-β1/2/3, activins, inhibins, BMPs (bone morphogenetic proteins), GDF (growth and differentiation factors), nodal, and AMH. They signal as dimers through type I and type II serine/threonine kinase receptor pairs, activating R-SMAD proteins (SMAD2/3 for TGF-β/activin; SMAD1/5/8 for BMPs) that translocate to the nucleus with SMAD4 to regulate transcription.

TGF-β therapeutic targeting: The dual role of TGF-β (tumor suppressor in early cancer, oncogenic driver later) complicates therapeutic targeting. Current approaches focus on using anti-TGF-β agents to overcome immunosuppression in combination with checkpoint inhibitors. Bintrafusp alfa (TGF-β trap + anti-PD-L1) is in clinical trials for multiple solid tumors.

BMP signaling: BMPs regulate bone formation, stem cell niches, and hematopoiesis. BMP4 maintains neural stem cell quiescence. Fibrodysplasia ossificans progressiva (FOP) is caused by constitutively active ACVR1/ALK2 (a BMP type I receptor) — causing heterotopic ossification; palovarotene and garetosmab are in trials.

Hepatocyte Growth Factor and MET Receptor

Hepatocyte growth factor (HGF; also called Scatter Factor, SF) is a large heterodimeric protein produced predominantly by stromal fibroblasts and platelets. Its receptor, MET (encoded by MET), is expressed on epithelial cells. HGF/MET signaling drives a biological program called "invasive growth" — coordinated proliferation, survival, motility, and morphogenesis that is critical for embryonic organ development and tissue regeneration but exploited by cancer for invasion and metastasis.

• MET activation modes: MET point mutations (exon 14 skipping mutations remove the juxtamembrane CBL-binding domain → impaired receptor degradation); MET amplification (gene copy number gain → ligand-independent constitutive activation); HGF autocrine/paracrine (especially in GBM, gastric, lung cancers).
• MET exon 14 NSCLC: METex14 skip mutations occur in ~3–4% of NSCLC. Tepotinib and capmatinib are FDA-approved MET inhibitors for METex14-mutant NSCLC, with ORR ~45–50%.
• MET amplification resistance: MET amplification is a major resistance mechanism to EGFR TKIs (~20% of T790M-negative resistance). Combining osimertinib + savolitinib (MET inhibitor) is under evaluation.
• HGF autocrine in glioblastoma: GBM cells produce both HGF and MET, creating an autocrine loop. HGF also activates VEGF production in GBM — explaining why anti-VEGF therapy (bevacizumab) combined with MET inhibition is being studied.