Tyrosinase-associated protein 1 (TYPR1), also known as CAS2, TYRP, TYRRP, or TRP1, plays an important role in melanin biosynthesis and can regulate or influence the type of melanin synthesized. It is a therapeutic target for melanoma.
(Data source: Hida T, et al. Int J Mol Sci. 2020)
TYRP1 expression distribution
In normal human tissues, TYRP1 expression exhibits significant tissue specificity, primarily confined to melanocytes in the skin, hair follicles, and eyes. In tumors, it is widely expressed mainly in melanomas, including cutaneous melanoma, acral melanoma, and uveal melanoma.
(Data source: uniprot)
(Data source: Hackett CS, et al. Mol Ther Oncol. 2024)
The structure of TYRP1 and its receptor
TYRP1 is a type I transmembrane glycoprotein, 537 amino acids in length, composed of multiple domains: a signal peptide at the N-terminus, a large intracellular melanosome domain (including a catalytic domain and a cysteine-rich domain), a single transmembrane α-helix, and a short C-terminal cytoplasmic tail. This structural organization enables TYRP1 to be properly anchored to the melanosome membrane and to interact effectively with its substrates and cofactors.
(Data source: Lai X, et al. Angew Chem Int Ed Engl. 2017)
The role of TYRP1 in melanin synthesis
In the melanin synthesis pathway, TYRP1 works in conjunction with two other key enzymes , tyrosinase (TYR) and dopachrome tautomerase (TYRP2/DCT). MITF initiates melanin production by activating the transcription of pigment genes TYR, TYRP1, DCT, and PMEL, which are transported from the trans-Golgi network to early/late endosomes to form melanosomes. Melanosomes have four maturation stages, characterized by their distinctive shape and quantity: eumelanin and pheomelanin. In the case of TYRP1, AP-1 and GGA play crucial roles in the sorting process from the trans-Golgi network through early/late endosomes to phase I melanosomes; these two mechanisms are: block-1/RAB32/RAB38/Varp/block-2; AP-1 or AP-3. RAB7 is essential for phase I melanosome formation and for TYRP1 sorting from early/late endosomes to phase I melanosomes.
(Data source) Hida T, et al. Int J Mol Sci. 2020)
Targeted therapy for TYRP1
Flanvotumab is a monoclonal antibody targeting TYRP1, developed by ImClone Systems for the treatment of malignant melanoma. It is currently in Phase I clinical trials, and there are no recent research updates.
TYRP1 is a promising target for treating various melanoma subtypes, particularly in patients unresponsive or resistant to current immunotherapies. TA99-CAR-T cells have demonstrated good antitumor activity and high safety in preclinical studies; in the NSG mouse model, TA99-CAR-T cells significantly inhibited SK-MEL-19 tumor growth. Although tumors were not completely eradicated, residual tumor cells still expressed TYRP1, indicating that antigen escape did not occur.
(Data source: Hackett CS, et al. Mol Ther Oncol. 2024)
