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Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
Wnt has become a substantial new target for drug development to treat cancer because of its signaling cascade that plays a central role in regulating significant functions of malignant epithelial cells. Wnt ligands and signals drive the Wnt signaling pathway through canonical (β-catenin dependent) or non-canonical (β-catenin independent) paths. The Wnt ligand binds to various transmembrane receptors, such as Frizzled (FZD), Receptor tyrosine kinases (RTKs) and Receptor tyrosine kinase-like orphan receptor (ROR) 1 or ROR2. The pathway is activated with the binding of Wnt ligand to its receptor, followed by the activation of β-catenin. In the absence of Wnt ligand, β-catenin undergoes phosphorylation by a destruction complex containing glycogen synthase kinase 3b (GSK3b), adenomatous polyposis coli (APC) and axin, followed by degradation of β-catenin.
Therapeutic approaches for targeting receptor tyrosine kinase like orphan receptor-1 in cancer cells
Published in Expert Opinion on Therapeutic Targets, 2019
Amin Kamrani, Amir Mehdizadeh, Majid Ahmadi, Leili Aghebati-Maleki, Mehdi Yousefi
ROR-1 (receptor tyrosine kinase orphan receptor-1) is a member of RTK superfamily. Fifty eight members of RTKs are classified into 20 different receptor families [8]. All RTKs have similar molecular anatomy containing an extracellular ligand binding domain, transmembrane region and intracellular TK domain [9]. ROR-1 is a type 1 transmembrane protein with 3 extracellular parts including Kringle domain(KNG), Cysteine-Rich Domain (CRD) (also known as Frizzled Domain(FZD)), immunoglobulin-like domain, transmembrane part, intracellular TK domain, proline-rich domain, and serin-threonin motif [10]. ROR-1 has located on chromosome 1p31-p32 encoding 937 amino acids (≈ 104 KDa). However, post-translational modification of ROR-1 adds numerous N-glycosylation regions causing the final protein molecular weight to be about 130KDa [5,11]. ‘Orphan’ is related to previously unknown ROR-1 ligands however, later studies revealed that ROR-1 has the ability to bind wnt5a probably via its extracellular CRD [12,13].