ALK: a protein involved in neurodevelopment (G238)

NCBI ID: G238

Content of Review Report on ALK Target / Biomarker

ALK

ALK: a protein involved in neurodevelopment

ALK is primarily found in the gut, CNS, and testes in adults. Activation of ALK occurs through ligand-mediated dimerization and subsequent autophosphorylation. However, in ALK-rearranged NSCLC, ALK activation can occur independently of ligand-mediation. ALK fusion proteins resulting from gene rearrangements lead to constitutive activation of downstream signaling pathways, including STAT3, mTOR, PI3K, Ras, and MEK. Resistance to ALK tyrosine kinase inhibitors (ALK-TKIs) can occur through various mechanisms, including cKIT gene amplification, HGF upregulation, and EGFR activation. Different ALK-TKIs, such as crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib, and entrectinib, have been developed to target ALK and have shown efficacy in ALK-positive NSCLC . Mutations in the kinase domain of ALK, particularly F1174, F1245, and R1275, are common in neuroblastoma. Overall, understanding the functional association and aberrant activation of ALK is crucial for developing targeted therapies and overcoming ALK-driven oncogenesis .
Based on the provided context information, the key viewpoints regarding ALK are as follows:

NPM-ALK SUMOylation: NPM-ALK forms heterodimers with wild-type NPM, which shuttle between the nucleus and cytoplasm. The association between NPM/NPM-ALK and SUMO proteins occurs predominantly in the nucleus, conferring stability to NPM-ALK and preventing its degradation. This SUMOylation-mediated stability leads to the accumulation and abundant expression of NPM-ALK in the nucleus and cytoplasm.

Current pre-clinically tested drugs in neuroblastoma: Several drugs have been tested against neuroblastoma, targeting various molecular pathways. These include inhibitors of ALK, Trk, and PI3K/AKT/mTOR pathway. Crizotinib is a well-known anti-ALK drug that showed promising results in patients with ALK dysregulation. Other compounds such as MLN8054, MLN8237, and GNF-4256 have also been tested as inhibitors of AURKA, TrkB, and PI3K/mTOR, respectively.

Oncogenic regulation of PD-L1: PD-L1 expression in cancer cells can be regulated by various oncogenes, including c-Myc, p53, EML4-ALK fusion gene, EGFR, and K-ras. These oncogenes can either positively or negatively regulate PD-L1 expression through distinct mechanisms.

In summary, the viewpoints related to ALK include its role in NPM-ALK SUMOylation and stability, the use of ALK inhibitors in neuroblastoma treatment, and the oncogenic regulation of PD-L1 expression by ALK and other oncogenes.

Protein Name: ALK Receptor Tyrosine Kinase

Functions: Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system (PubMed:11121404, PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385, PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673). In contrast, ALKAL1 is not a potent physiological ligand for ALK (PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:34819673). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150). Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403, PubMed:16878150). ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760, PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation (PubMed:11278720, PubMed:11809760, PubMed:12107166). MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction (PubMed:12122009). Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (PubMed:15226403, PubMed:16878150)

The "ALK Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about ALK comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
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