# YES1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- YES1 encodes a non-receptor protein tyrosine kinase crucial for signal transduction downstream of receptor tyrosine kinases, integrins, and GPCRs, mediating mitogenic, survival, and migratory signals.
- Genomic amplification of YES1 at locus 18p11.32 is a recurrent oncogenic event in squamous cell carcinomas (lung, head/neck), gastric cancer, and melanoma, leading to significantly elevated mRNA expression.
- YES1 acts as a key mediator in acquired resistance to targeted therapies, notably EGFR inhibitors in non-small cell lung cancer and CDK4/6 inhibitors in breast cancer, by activating alternative signaling pathways like MAPK and PI3K/AKT.
- The protein's structure features a unique N-terminal domain, SH3, SH2, and kinase domains, with critical regulatory phosphorylation sites at Tyr416 (activation) and Tyr530 (inhibition by CSK).
- Multi-kinase inhibitors like dasatinib and bosutinib exhibit potent YES1 inhibitory activity, with dasatinib binding to the ATP-binding pocket in the DFG-in conformation, offering a therapeutic avenue for YES1-driven cancers.
- YES1 also plays a role in immune evasion by phosphorylating PD-L1, enhancing its cell-surface expression, suggesting potential for combination therapy with immune checkpoint inhibitors.

---

## Executive Summary & Key Metadata

The **YES1** gene (Yamaguchi sarcoma virus oncogene homolog 1) encodes a non-receptor protein tyrosine kinase belonging to the Src family kinases (SFKs). YES1 is a critical transducer of mitogenic, survival, and migratory signals downstream of receptor tyrosine kinases (RTKs), integrins, and G-protein-coupled receptors (GPCRs). Its deregulation—through genomic amplification, transcriptional upregulation, or post-translational modification—is a recurrent feature of multiple solid tumors, including squamous cell carcinomas of the lung and head/neck, gastric cancer, and melanoma. YES1 has also emerged as a mechanism of acquired resistance to targeted therapies, notably to EGFR inhibitors and CDK4/6 inhibitors.

| **Attribute** | **Value** |
|---|---|
| **HGNC Symbol** | YES1 |
| **UniProt Accession** | P07947 |
| **Representative PDB ID** | 2HDA (human YES1 kinase domain in complex with a pyrazolopyrimidine inhibitor) |
| **Chromosomal Locus** | 18p11.32 (GRCh38: chr18:7,128,790–7,242,337; minus strand) |
| **Primary Molecular Function** | Non-receptor protein tyrosine kinase; signal transduction downstream of RTKs, integrins, and immune receptors |
| **Disease & Pathology Associations** | Squamous cell carcinoma (lung, head/neck), gastric cancer, melanoma, breast cancer; resistance to EGFR and CDK4/6 inhibitors |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Architecture

YES1 is located on the short arm of chromosome 18 at band 11.32 (18p11.32). The gene spans approximately 113.5 kilobases (kb) of genomic DNA on the minus (reverse) strand of GRCh38 (chr18:7,128,790–7,242,337). The genomic structure comprises 11 exons and 10 introns, with the translation initiation codon (ATG) located in exon 2 and the stop codon in exon 11. The 5' untranslated region (UTR) is encoded by exon 1 and part of exon 2, while the 3' UTR is exceptionally long (~2.8 kb) and contains multiple AU-rich elements (AREs) that confer mRNA instability, permitting rapid downregulation of YES1 transcript in response to cellular stress.

The promoter region of YES1 lacks a canonical TATA box but contains a high-density CpG island spanning approximately 1.2 kb upstream of the transcription start site (TSS). This CpG island is a target for DNA methylation-mediated silencing; hypermethylation of this region has been observed in some normal tissues, whereas hypomethylation correlates with transcriptional activation in malignant cells. Multiple Sp1 binding sites (GC boxes) are clustered within the proximal promoter (−200 to −50 bp relative to TSS), and these are essential for basal transcriptional activity. Additionally, a functional E-box motif (CANNTG) at position −310 bp serves as a binding site for MYC, which directly transactivates YES1 expression in MYC-driven tumors.

### 1.2 Enhancer Elements and Chromatin Architecture

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data from the ENCODE project reveal that the YES1 locus is embedded within a topologically associating domain (TAD) that also contains the neighboring genes *TYMS* (thymidylate synthetase) and *ENOSF1*. Active enhancer marks (H3K27ac, H3K4me1) are enriched at two intergenic regions: one located ~15 kb upstream of the TSS and another within intron 1. The intron 1 enhancer has been shown to physically interact with the promoter via chromatin looping, and this interaction is reinforced by the architectural protein CTCF, which binds at the boundaries of the TAD. In squamous cell carcinoma cell lines, copy-number gain of 18p11.32 leads to amplification of both the promoter and the intronic enhancer, resulting in a 5- to 20-fold increase in YES1 mRNA expression relative to normal epithelial cells.

### 1.3 Alternative Splicing and Isoforms

The YES1 gene undergoes alternative splicing to generate at least three transcript variants, although only one produces a catalytically active full-length protein:

- **Transcript Variant 1 (NM_005433.4)**: Encodes the canonical 543-amino-acid YES1 protein (UniProt P07947-1). This is the dominant isoform in all tissues and is the sole isoform with demonstrated tyrosine kinase activity.
- **Transcript Variant 2 (NM_001291459.2)**: Retains intron 7, introducing a premature stop codon. The resulting protein is truncated at the C-terminus, lacking the kinase domain and the C-terminal regulatory tail. This isoform is predicted to be a dominant-negative regulator, but its endogenous expression is extremely low and restricted to testicular tissue.
- **Transcript Variant 3 (NM_001291460.2)**: Uses an alternative 3' splice acceptor site in exon 9, resulting in an in-frame deletion of 12 amino acids within the kinase domain (residues 380–391). This deletion disrupts the αF-αG helix interface, reducing catalytic activity by ~70% in in vitro kinase assays. The physiological relevance of this isoform remains unclear.

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Domain Organization

The YES1 protein (543 amino acids; molecular weight ~60.8 kDa) adopts the canonical Src-family kinase architecture, comprising four distinct structural domains arranged from the N-terminus to the C-terminus:

1. **Unique N-terminal domain (residues 1–80)**: This is the most divergent region among SFK members. It contains a myristoylation motif (MGSSKSK) at residues 1–7, where glycine at position 2 is covalently modified with myristic acid. This lipid modification is essential for membrane anchoring. Additionally, residues 38–80 contain a cluster of basic amino acids (lysine and arginine) that mediate electrostatic interactions with negatively charged phospholipids, particularly phosphatidylinositol-4,5-bisphosphate (PIP2), on the inner leaflet of the plasma membrane.

2. **SH3 domain (residues 81–140)**: A ~60-residue module composed of five antiparallel β-strands arranged in a β-barrel fold. The SH3 domain recognizes proline-rich motifs with the consensus sequence PXXP. In YES1, the SH3 domain binds to the linker region between the SH2 and kinase domains in the autoinhibited conformation, as well as to proline-rich sequences in substrates such as the focal adhesion kinase (FAK) and the adaptor protein p130Cas.

3. **SH2 domain (residues 141–250)**: A ~110-residue domain consisting of a central antiparallel β-sheet flanked by two α-helices. The SH2 domain binds phosphotyrosine (pTyr) residues in the context of specific C-terminal flanking sequences. For YES1, the preferred binding motif is pYEEI (phosphotyrosine-glutamate-glutamate-isoleucine). In the autoinhibited state, the SH2 domain binds to the phosphorylated C-terminal tail (pTyr530). Upon dephosphorylation of Tyr530, the SH2 domain becomes available to engage phosphotyrosine motifs on activated RTKs (e.g., EGFR, PDGFR) and adaptor proteins.

4. **Kinase domain (residues 251–520)**: The bilobal catalytic domain. The N-lobe (residues 251–340) consists of a five-stranded β-sheet and a single α-helix (αC). The C-lobe (residues 341–520) is predominantly α-helical and contains the activation loop (A-loop, residues 410–435). Key catalytic residues include:
   - **Lys295** (β3 strand): Forms a salt bridge with Glu310 (αC helix) to stabilize the active conformation; also coordinates the α- and β-phosphates of ATP.
   - **Glu310** (αC helix): Part of the conserved VAVK motif; its interaction with Lys295 is required for catalytic competence.
   - **Asp386** (HRD motif): Catalytic base that accepts a proton from the substrate tyrosine hydroxyl group.
   - **Asn391** (HRD motif): Coordinates a magnesium ion essential for ATP binding.
   - **Tyr416** (A-loop): Autophosphorylation site; phosphorylation of this residue stabilizes the active conformation of the A-loop.
   - **Tyr530** (C-terminal tail): Phosphorylation by C-terminal Src kinase (CSK) promotes the autoinhibited conformation.

5. **C-terminal regulatory tail (residues 521–543)**: Contains the critical Tyr530 residue. When phosphorylated, this tail folds back to engage the SH2 domain, locking the kinase in an inactive "closed" conformation.

### 2.2 Autoinhibited and Active Conformations

The crystal structure of YES1 (PDB: 2HDA) reveals the molecular basis of its regulation. In the inactive state, the SH2 domain binds pTyr530, while the SH3 domain engages a polyproline type II helix formed by the SH2-kinase linker (residues 245–250). This dual engagement clamps the kinase domain in a distorted conformation where the αC helix is rotated outward, breaking the Lys295–Glu310 salt bridge. The A-loop is partially unwound, blocking the substrate-binding cleft.

Activation proceeds through a two-step mechanism:
1. **Dephosphorylation of Tyr530** by protein tyrosine phosphatases (e.g., PTP1B, SHP2) releases the SH2 domain from the C-terminal tail.
2. **Autophosphorylation of Tyr416** in the A-loop stabilizes the active conformation, where the αC helix is rotated inward, the Lys295–Glu310 salt bridge is formed, and the A-loop adopts an extended conformation that permits substrate binding.

### 2.3 Interactive 3D Visualizer

[Interactive 3D Protein Visualizer: Load YES1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P07947)

The visualizer tool allows users to explore the YES1 kinase domain (PDB: 2HDA) in atomic detail. Key features to examine include:
- The ATP-binding pocket at the interface of the N- and C-lobes, where type I inhibitors (e.g., dasatinib) bind.
- The DFG motif (Asp404-Phe405-Gly406) at the base of the A-loop, which adopts distinct conformations in active (DFG-in) versus inactive (DFG-out) states.
- The myristate-binding pocket in the C-lobe, which is a target for allosteric inhibitors.

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Upstream Activation Mechanisms

YES1 is activated by a diverse array of extracellular stimuli. The most well-characterized activation pathway involves RTKs:

- **EGFR (ErbB1) and HER2 (ErbB2)**: Upon ligand (EGF, TGFα) binding, EGFR dimerizes and autophosphorylates on multiple tyrosine residues. YES1 SH2 domain binds to pTyr992 and pTyr1173 of EGFR, bringing YES1 into proximity for phosphorylation at Tyr416 by EGFR or by trans-autophosphorylation. This physical association is critical for EGF-induced cell proliferation and migration.
- **PDGFR (Platelet-Derived Growth Factor Receptor)**: YES1 binds to pTyr751 of PDGFRβ and mediates PDGF-stimulated chemotaxis in fibroblasts.
- **Integrin signaling**: Engagement of integrins with extracellular matrix proteins (fibronectin, collagen) triggers focal adhesion assembly. YES1 is recruited to focal adhesions via its SH3 domain interaction with FAK. FAK phosphorylates YES1 at Tyr416, and YES1 in turn phosphorylates p130Cas (BCAR1) at multiple tyrosine residues, promoting Rac1 activation and cell motility.
- **GPCR signaling**: G-protein-coupled receptors (e.g., β2-adrenergic receptor) can transactivate YES1 through a Src-family kinase-dependent pathway involving β-arrestin scaffolds.

### 3.2 Downstream Effector Pathways

Once activated, YES1 phosphorylates a broad spectrum of substrates, propagating signals through several canonical pathways:

1. **MAPK/ERK pathway**: YES1 phosphorylates the adaptor protein SHC (SHC1) at Tyr239/240, creating docking sites for the GRB2-SOS complex. This recruits SOS to the plasma membrane, where it catalyzes nucleotide exchange on RAS, leading to sequential activation of RAF, MEK1/2, and ERK1/2. ERK translocates to the nucleus and phosphorylates transcription factors (ELK1, MYC, FOS) that drive cell cycle progression.

2. **PI3K/AKT pathway**: YES1 phosphorylates the p85 regulatory subunit of PI3K, enhancing its association with the p110 catalytic subunit. PI3K generates PIP3 at the membrane, recruiting AKT via its PH domain. AKT phosphorylates downstream targets including TSC2 (inhibiting the TSC1/TSC2 complex), MDM2 (promoting p53 degradation), and BAD (inhibiting apoptosis).

3. **STAT3 signaling**: YES1 directly phosphorylates STAT3 at Tyr705, promoting its dimerization and nuclear translocation. Nuclear STAT3 upregulates genes involved in survival (BCL2, MCL1), proliferation (CCND1, MYC), and angiogenesis (VEGFA).

4. **Focal adhesion turnover**: YES1 phosphorylates paxillin (PXN) at Tyr31 and Tyr118, which is required for focal adhesion disassembly and cell migration. YES1 also phosphorylates FAK at Tyr861, enhancing FAK catalytic activity.

### 3.3 Negative Regulation and Feedback Loops

YES1 activity is tightly controlled by multiple mechanisms:

- **C-terminal Src kinase (CSK)**: CSK phosphorylates Tyr530, promoting the autoinhibited conformation. CSK is recruited to the plasma membrane by the adaptor protein CBP (PAG1), which itself is a substrate of SFKs, creating a negative feedback loop.
- **Protein tyrosine phosphatases**: PTP1B (PTPN1) and SHP2 (PTPN11) dephosphorylate Tyr530, activating YES1. Conversely, PTPα (PTPRA) dephosphorylates Tyr416, inactivating the kinase.
- **Ubiquitin-proteasome degradation**: YES1 is ubiquitinated by the E3 ligase CBL (Casitas B-lineage lymphoma), which recognizes phosphorylated YES1 bound to activated RTKs. Ubiquitination at Lys residues within the kinase domain targets YES1 for proteasomal degradation.
- **MicroRNA-mediated regulation**: miR-34a and miR-203 directly target the 3' UTR of YES1 mRNA, reducing its translation. These miRNAs are frequently silenced by promoter hypermethylation in cancers, contributing to YES1 overexpression.

### 3.4 Protein-Protein Interaction Network

BioGRID lists over 120 physical interactors for YES1. Key nodes in the interaction network include:

| **Interactor** | **Interaction Type** | **Functional Consequence** |
|---|---|---|
| EGFR | SH2-phosphotyrosine | Activation of YES1; EGFR signaling amplification |
| FAK (PTK2) | SH3-proline-rich | Focal adhesion signaling; cell migration |
| p130Cas (BCAR1) | Substrate | Cell motility; invasion |
| SHC1 | Substrate | MAPK pathway activation |
| STAT3 | Substrate | Transcriptional regulation |
| CSK | Enzyme-substrate | Inactivation via Tyr530 phosphorylation |
| CBL | E3 ligase | Ubiquitination and degradation |
| PAG1 (CBP) | Scaffold | Membrane recruitment of CSK |
| GRB2 | SH2/SH3 adaptor | RAS-MAPK pathway coupling |
| PXN (Paxillin) | Substrate | Focal adhesion turnover |

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Somatic Mutations in Cancer

Unlike some oncogenes (e.g., KRAS, BRAF) that harbor recurrent activating point mutations, YES1 is rarely mutated in its kinase domain. Instead, the predominant mechanism of YES1 deregulation in cancer is **genomic amplification** and **transcriptional upregulation**. However, a small number of recurrent somatic mutations have been cataloged in COSMIC:

- **p.Gly241Arg (G241R)**: Located in the SH2 domain at the phosphotyrosine-binding pocket. This mutation reduces the affinity of SH2 for pTyr530, destabilizing the autoinhibited conformation and leading to constitutive kinase activity. Reported in a single case of gastric adenocarcinoma.
- **p.Arg78Cys (R78C)**: Located in the unique domain near the myristoylation site. This mutation does not affect catalytic activity but alters membrane localization, increasing the fraction of YES1 associated with detergent-resistant membrane microdomains (lipid rafts). Observed in melanoma.
- **p.Pro525Leu (P525L)**: Located in the C-terminal tail adjacent to Tyr530. This mutation disrupts the SH2-binding motif (pYEEI-like sequence), preventing intramolecular engagement of the SH2 domain and locking YES1 in an active conformation. Reported in a lung squamous cell carcinoma sample.
- **p.Glu310Lys (E310K)**: A kinase domain mutation that disrupts the Lys295-Glu310 salt bridge. Paradoxically, this mutation reduces catalytic activity but promotes YES1 dimerization, leading to trans-phosphorylation of other SFK members. Functional studies are ongoing.

### 4.2 Germline Variants and Inherited Disease

No germline pathogenic variants in YES1 have been associated with Mendelian disorders. Common single-nucleotide polymorphisms (SNPs) in the YES1 locus (e.g., rs10493112 in intron 3) have been nominally associated with altered risk for colorectal cancer in genome-wide association studies, but these findings have not been consistently replicated.

### 4.3 YES1 Amplification as a Biomarker

Focal amplification of 18p11.32, encompassing YES1, is observed in approximately 10–15% of lung squamous cell carcinomas, 8% of head and neck squamous cell carcinomas, and 5% of gastric cancers. High-level YES1 amplification (copy number >6) correlates with poor overall survival in lung squamous cell carcinoma patients. In addition, YES1 mRNA overexpression without genomic amplification is common, driven by MYC transactivation or loss of miR-34a/miR-203 expression.

### 4.4 Differential Diagnosis in Clinical Genomics

When YES1 amplification is detected by next-generation sequencing or fluorescence in situ hybridization, the following differential diagnoses should be considered:

- **EGFR amplification** (7p11.2): Co-amplification of EGFR and YES1 occurs in ~30% of YES1-amplified lung squamous cell carcinomas. This co-amplification has therapeutic implications, as dual EGFR/SFK inhibition may be required.
- **FGFR1 amplification** (8p11.23): FGFR1 amplification is a mutually exclusive event with YES1 amplification in lung squamous cell carcinoma, suggesting distinct oncogenic driver pathways.
- **SRC amplification** (20q11.23): SRC is a paralog of YES1; amplification of SRC can phenocopy YES1 activation and should be ruled out when YES1-targeted therapy is considered.

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Oncoproteins

YES1 was originally identified as the cellular homolog of the v-Yes oncoprotein encoded by the Yamaguchi sarcoma virus (a member of the avian sarcoma virus group). The viral protein v-Yes lacks the C-terminal regulatory tail containing Tyr530, rendering it constitutively active. This discovery was foundational for understanding SFK regulation.

In human pathology, YES1 interacts with several viral oncoproteins:

- **Human Papillomavirus (HPV) E6**: The high-risk HPV E6 protein binds to the SH3 domain of YES1 via a PXXP motif in E6. This interaction promotes YES1 activation and enhances E6-mediated degradation of p53. In HPV-positive head and neck squamous cell carcinoma, YES1 expression is significantly elevated compared to HPV-negative tumors.
- **Epstein-Barr Virus (EBV) LMP2A**: The latent membrane protein 2A (LMP2A) of EBV contains an immunoreceptor tyrosine-based activation motif (ITAM) that is phosphorylated by SFKs, including YES1. YES1 binds to phosphorylated LMP2A, contributing to B-cell survival signaling in EBV-associated lymphomas.
- **Hepatitis B Virus (HBV) HBx**: The HBx protein of HBV activates YES1 through a calcium-dependent pathway, promoting hepatocyte proliferation during chronic infection. This may contribute to hepatocellular carcinoma development.

### 5.2 Bacterial Effectors

- **Helicobacter pylori CagA**: The CagA oncoprotein is delivered into gastric epithelial cells via a type IV secretion system. Once inside, CagA is phosphorylated by SFKs, including YES1, at EPIYA motifs. Phosphorylated CagA activates SHP2 phosphatase, driving aberrant cell proliferation and contributing to gastric carcinogenesis. YES1 knockdown in gastric epithelial cells attenuates CagA-mediated signaling.

### 5.3 Immune Evasion Mechanisms

YES1 has been implicated in the regulation of immune checkpoint molecules. In melanoma cells, YES1 phosphorylates PD-L1 (CD274) at Tyr112, which is required for PD-L1 glycosylation and stable cell-surface expression. Inhibition of YES1 with dasatinib reduces PD-L1 surface levels, enhancing T-cell-mediated killing. This positions YES1 as a potential target for combination immunotherapy strategies.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 FDA-Approved Inhibitors with YES1 Activity

No drug is currently approved specifically for YES1 inhibition. However, several multi-kinase inhibitors with potent YES1 activity are FDA-approved for other indications:

| **Drug** | **Targets** | **IC50 for YES1** | **Approved Indications** |
|---|---|---|---|
| **Dasatinib** | BCR-ABL, SRC, YES1, KIT, PDGFRβ | 0.5 nM | Chronic myeloid leukemia; acute lymphoblastic leukemia |
| **Bosutinib** | BCR-ABL, SRC, YES1 | 1.2 nM | Chronic myeloid leukemia |
| **Saracatinib (AZD0530)** | SRC, YES1, ABL | 2.7 nM | Investigational (failed Phase III for ovarian cancer) |
| **Ponatinib** | BCR-ABL, SRC, YES1, FGFR, VEGFR | 5.4 nM | Chronic myeloid leukemia; Philadelphia-positive ALL |

Dasatinib is the most extensively studied YES1 inhibitor in solid tumors. It binds to the ATP-binding pocket of YES1 in the DFG-in conformation (type I inhibitor), forming a hydrogen bond with the hinge region (Met319) and occupying the adenine-binding site.

### 6.2 Investigational Agents and Resistance Mechanisms

- **Allosteric inhibitors**: Compounds targeting the myristate-binding pocket of SFKs (e.g., compound 1, a pyrazolopyrimidine derivative) have shown selectivity for YES1 over SRC. These agents stabilize the autoinhibited conformation and are in preclinical development.
- **PROTACs (Proteolysis-Targeting Chimeras)**: Dasatinib-based PROTACs that recruit the E3 ligase VHL or CRBN to YES1 have been developed. These agents induce proteasomal degradation of YES1 and show enhanced antiproliferative activity in YES1-amplified cancer cell lines compared to dasatinib alone.
- **Resistance to EGFR inhibitors**: YES1 amplification is a documented mechanism of acquired resistance to osimertinib (third-generation EGFR inhibitor) in EGFR-mutant non-small cell lung cancer. In resistant cells, YES1 activates the ERK pathway independently of EGFR, maintaining cell survival. Combination of osimertinib with dasatinib overcomes resistance in preclinical models.
- **Resistance to CDK4/6 inhibitors**: YES1 overexpression confers resistance to palbociclib and ribociclib in breast cancer cell lines. YES1 phosphorylates RB1 at non-canonical sites, promoting its inactivation and bypassing the G1/S checkpoint. Clinical trials combining CDK4/6 inhibitors with dasatinib are being planned.

### 6.3 Pharmacogenomic Considerations

- **CYP3A4 metabolism**: Dasatinib is metabolized primarily by CYP3A4. Co-administration with strong CYP3A4 inhibitors (ketoconazole, clarithromycin) increases dasatinib exposure by ~5-fold, requiring dose reduction. Conversely, CYP3A4 inducers (rifampin, phenytoin) reduce exposure.
- **ABCG2 (BCRP) transporter**: YES1 inhibitors are substrates of the efflux transporter ABCG2. Polymorphisms in ABCG2 (e.g., Q141K) can alter drug accumulation in tumor cells, affecting therapeutic response.
- **Biomarker-driven patient selection**: Clinical trials of dasatinib in solid tumors have largely failed due to unselected patient populations. Retrospective analyses suggest that patients with YES1-amplified tumors (copy number ≥6) or high YES1 mRNA expression (top quartile) derive the greatest benefit. Prospective biomarker-driven trials are warranted.

---

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession / Identifier** | **URL** |
|---|---|---|
| NCBI Gene | 7525 | https://www.ncbi.nlm.nih.gov/gene/7525 |
| Ensembl | ENSG00000176105 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000176105 |
| UniProt | P07947 | https://www.uniprot.org/uniprotkb/P07947/entry |
| RCSB PDB | 2HDA | https://www.rcsb.org/structure/2HDA |
| OMIM | 164880 | https://www.omim.org/entry/164880 |
| ClinVar | YES1 | https://www.ncbi.nlm.nih.gov/clinvar/?term=YES1 |
| COSMIC | YES1 | https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=YES1 |
| BioGRID | 113628 | https://thebiogrid.org/113628 |
| STRING | 7525 (Homo sapiens) | https://string-db.org/network/9606.ENSP00000304895 |
| Gene Ontology (GO) | GO:0004713 (protein tyrosine kinase activity); GO:0000165 (MAPK cascade); GO:0005737 (cytoplasm) | https://www.ebi.ac.uk/QuickGO/ |

### Gene Ontology Terms

| **Ontology** | **Term** | **Accession** |
|---|---|---|
| Molecular Function | Protein tyrosine kinase activity | GO:0004713 |
| Molecular Function | ATP binding | GO:0005524 |
| Molecular Function | SH2 domain binding | GO:0042169 |
| Biological Process | Cell migration | GO:0016477 |
| Biological Process | Positive regulation of cell proliferation | GO:0008284 |
| Biological Process | Peptidyl-tyrosine phosphorylation | GO:0018108 |
| Cellular Component | Cytoplasm | GO:0005737 |
| Cellular Component | Plasma membrane | GO:0005886 |
| Cellular Component | Focal adhesion | GO:0005925 |

---

## 8. Signaling Pathway Diagram

The following Mermaid diagram illustrates the core YES1 signaling network and its integration with oncogenic pathways:

```mermaid
sequenceDiagram
    participant L as "Ligand (EGF, PDGF)"
    participant R as "RTK (EGFR, PDGFR)"
    participant Y as "YES1 (inactive)"
    participant Y* as YES1 (active)
    participant P as "Phosphatase (PTP1B, SHP2)"
    participant C as "CSK"
    participant S as "Substrates (SHC, FAK, STAT3)"
    participant D as "Downstream (MAPK, PI3K/AKT)"
    participant T as "Transcription (MYC, CCND1)"
    L->>R: Ligand binding
    R->>R: Autophosphorylation (pTyr)
    R->>Y: SH2 domain binds pTyr
    P->>Y: Dephosphorylate Tyr530
    Y->>Y*: Autophosphorylate Tyr416
    Y*->>S: Phosphorylate substrates
    S->>D: Activate MAPK, PI3K/AKT
    D->>T: Phosphorylate transcription factors
    T->>T: Upregulate proliferation genes
    C->>Y: Phosphorylate Tyr530 (inactivation)
    Y*->>R: Phosphorylate RTK (feedback)
```

---

## 9. Conclusion

YES1 is a multifaceted non-receptor tyrosine kinase whose structural biology, signaling networks, and clinical implications have been extensively characterized. The protein's modular domain architecture—unique N-terminus, SH3, SH2, kinase, and regulatory tail—enables precise spatiotemporal control of its activity. Genomic amplification of YES1 at 18p11.32 is a recurrent oncogenic event in squamous cell carcinomas and other solid tumors, and YES1 activation contributes to therapeutic resistance across multiple targeted agents. While no YES1-specific inhibitor has been approved, repurposing of multi-kinase inhibitors such as dasatinib, combined with biomarker-driven patient selection, represents a promising therapeutic strategy. Future research should focus on developing selective YES1 inhibitors and understanding the context-dependent functions of YES1 in tumor immunity and metastasis.

---

## Related Clinical & Scientific Guides

* [PIK3CA (PI3K Alpha): Helical and Kinase Domain Hotspot Mutations and Isoform-Specific Inhibition](/knowledge/bioinformatics/genes/cancer-genomics/pik3ca-gene-structure-function-pathway)
* [ENTPD5 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/entpd5-gene-structure-function-pathway)
* [PDGFB Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/pdgfb-gene-structure-function-pathway)


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