YES1

Official Full Name

YES proto-oncogene 1, Src family tyrosine kinase

Organism

Homo sapiens

GeneID

7525

Background

This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22. [provided by RefSeq, Jul 2008]

Synonyms

Yes; c-yes; HsT441; P61-YES;

Bio Chemical Class

Kinase

Protein Sequence

MGCIKSKENKSPAIKYRPENTPEPVSTSVSHYGAEPTTVSPCPSSSAKGTAVNFSSLSMTPFGGSSGVTPFGGASSSFSVVPSSYPAGLTGGVTIFVALYDYEARTTEDLSFKKGERFQIINNTEGDWWEARSIATGKNGYIPSNYVAPADSIQAEEWYFGKMGRKDAERLLLNPGNQRGIFLVRESETTKGAYSLSIRDWDEIRGDNVKHYKIRKLDNGGYYITTRAQFDTLQKLVKHYTEHADGLCHKLTTVCPTVKPQTQGLAKDAWEIPRESLRLEVKLGQGCFGEVWMGTWNGTTKVAIKTLKPGTMMPEAFLQEAQIMKKLRHDKLVPLYAVVSEEPIYIVTEFMSKGSLLDFLKEGDGKYLKLPQLVDMAAQIADGMAYIERMNYIHRDLRAANILVGENLVCKIADFGLARLIEDNEYTARQGAKFPIKWTAPEAALYGRFTIKSDVWSFGILQTELVTKGRVPYPGMVNREVLEQVERGYRMPCPQGCPESLHELMNLCWKKDPDERPTFEYIQSFLEDYFTATEPQYQPGENL

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

YES1 (YES Proto-Oncogene 1) is a member of the SRC family of non-receptor tyrosine kinases (SFKs) and is localized on the inner side of the plasma membrane, anchored to lipid rafts via N-terminal myristoylation. Its structure comprises SH3 (protein–protein interaction), SH2 (phosphotyrosine binding), and kinase domains. Activation requires dephosphorylation of the C-terminal tyrosine (Tyr537) and autophosphorylation of Tyr426 within the kinase domain.

Figure 1. Functional domains of YES1. (Kook E, et al., 2024)

Upstream Regulation

YES1 is regulated by multiple upstream signals. Receptor tyrosine kinases (RTKs) such as EGFR and PDGFR recruit YES1 to their intracellular domains upon activation, leading to phosphorylation of downstream substrates involved in cell adhesion and migration. The cellular microenvironment also influences YES1 activity; extracellular matrix stiffness activates YES1 via the integrin-FAK axis to promote actin remodeling. In T cells, chemokines like CXCL12 induce phosphorylation of substrates such as DPYSL2, driving immune cell migration.

Key Substrates

YES1 phosphorylates several critical substrates. These include junctional proteins such as PARD3, involved in tight junction assembly, and CTNND1 (β-catenin), which stabilizes adhesion complexes. It also targets metabolic transporters like OCT2 to enhance substrate transport, and cell cycle regulators such as CDK4, where Thr172 phosphorylation promotes G1/S progression.

Pathological Roles and Therapy Resistance

YES1 exhibits oncogenic properties in solid tumors. Its overexpression promotes proliferation, migration, and invasion through mechanisms including aberrant centrosome regulation via AURKA phosphorylation, PI3K/AKT pathway activation suppressing apoptosis, and nuclear EGFR translocation, enhancing DNA repair, which may contribute to chemotherapy resistance. YES1 also functions as a resistance mediator in targeted therapy; in non-small cell lung cancer, it can drive cetuximab resistance through EGFR Tyr992 phosphorylation and nuclear translocation. In HER2-positive breast cancer, YES1 forms a positive feedback loop with ERBB2, reducing sensitivity to HER2-targeted inhibitors.

Figure 2. Role of YES1 signaling in resistance to targeted therapy and chemotherapy. (Zhou H, et al., 2023)

Targeted Therapy Approaches

Efforts to inhibit YES1 focus on two main categories. Pan-SFK inhibitors such as dasatinib block YES1 along with other SFKs, showing substantial tumor regression in YES1-amplified models, although clinical utility is limited by off-target toxicity. Selective YES1 inhibitors, exemplified by CH6953755, bind the kinase hinge region and achieve nanomolar inhibition with significantly reduced activity against SRC, lowering the risk of myelosuppression.

Innovative strategies include antibody–drug conjugates (ADCs), such as TAK-180, which deliver cytotoxic payloads via lysosome-cleavable linkers, and microRNA replacement therapy using miR-140-5p mimics to downregulate YES1 expression, thereby reducing tumor growth and reversing chemoresistance. Future development will require integrating YES1 gene amplification or mutation screening to define responsive patient populations and exploring interactions with the immune microenvironment.

Reference

Garmendia I, Redin E, Montuenga LM, et al. YES1: A Novel Therapeutic Target and Biomarker in Cancer. Mol Cancer Ther. 2022 Sep 6;21(9):1371-1380.
Zhou H, Sun D, Tao J, et al. Role of YES1 signaling in tumor therapy resistance. Cancer Innov. 2023 Mar 3;2(3):210-218.
Kook E, Chun KS, Kim DH. Emerging Roles of YES1 in Cancer: The Putative Target in Drug Resistance. Int J Mol Sci. 2024 Jan 25;25(3):1450.

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