![]() Binding of Wnt5a to ROR1 and/or ROR2 can induce receptor homo- or hetero-dimerization to activate the signaling of AKT/ERK, Rho GTPases, NF-κB, and STAT3 pathways resulting in cell survival, proliferation, differentiation, and migration. The oncogenic functions of these receptors can be unleashed through amplification and overexpression via transcriptionally regulated mechanisms, and elevated ROR1, ROR2, and PTK7 expression is linked to tumor development and metastasis in several hematological as well as solid malignancies. ĭespite their status as “dead” enzymes, these Wnt-binding RTKs are dysregulated in multiple diseases such as cancer and developmental disorders. Structural and biochemical analysis of their pseudokinase domains revealed a close resemblance to the autoinhibited kinase domain of the insulin receptor however, these molecules are capable of modulating signaling through conformational dynamics. These receptors are also considered to be pseudokinases due to their (pseudo)kinase domain sequence deviations from the canonical kinase domain motifs. A distinct subfamily of RTKs comprises of Wnt receptors, such as receptor tyrosine kinase orphan-like receptor 1 and 2 (ROR1/2) and protein tyrosine kinase 7 (PTK7). Receptor tyrosine kinases (RTKs) are transmembrane proteins that relay growth-factor signals to sustain a diverse set of biological responses from cell proliferation to apoptosis and differentiation. Our findings bring new insight into the molecular mechanisms of ROR1, ROR2, and PTK7, and highlight the therapeutic potential of targeting ROR1 with small molecule inhibitors binding to its vestigial ATP-binding site. To probe the pharmacological modulation of ROR1 oncogenic signaling, we used affinity purification coupled to mass spectrometry (AP-MS) and proximity-dependent biotin identification (BioID) to map its interactome before and after binding of GZD824, a small molecule inhibitor previously shown to bind to the ROR1 pseudokinase domain. ![]() We also demonstrate that the distal C-terminal regions of ROR1 and ROR2 are required for receptors stability and downstream signaling. Functionally, we show that ROR1 expression enhances cell survival and Wnt-mediated cell proliferation, while ROR2 and PTK7 expression is linked to cell migration. We applied proteomic profiling to BaF3 clones and identified distinctive roles for ROR1, ROR2, and PTK7 pseudokinases in modulating the expression of proteins involved in cytoskeleton dynamics, apoptotic, and metabolic signaling. ![]() Here, we developed a cellular model by stably expressing ROR1, ROR2, and PTK7 in BaF3 cells that allowed us to readily investigate side-by-side their signaling capability and functional outcome. Wnt5a ligand can activate these receptors, but lead to divergent signaling and functional outcomes through mechanisms that remain largely unknown. However, their overexpression in adult tissue is strongly connected to tumor development and metastasis, suggesting a strong pharmacological potential for these molecules. Despite their lack of catalytic activity, these receptors regulate skeletal, cardiorespiratory, and neurological development during embryonic and fetal stages. ROR1, ROR2, and PTK7 are Wnt ligand-binding members of the receptor tyrosine kinase family. ![]()
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