ABL1

Official Full Name

ABL proto-oncogene 1, non-receptor tyrosine kinase

Organism

Homo sapiens

GeneID

Background

This gene is a protooncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of the protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene. The ubiquitously expressed protein has DNA-binding activity that is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function. This gene has been found fused to a variety of translocation partner genes in various leukemias, most notably the t(9;22) translocation that results in a fusion with the 5' end of the breakpoint cluster region gene (BCR; MIM:151410). Alternative splicing of this gene results in two transcript variants, which contain alternative first exons that are spliced to the remaining common exons. [provided by RefSeq, Aug 2014]

Synonyms

ABL; JTK7; p150; c-ABL; v-abl; CHDSKM; c-ABL1; BCR-ABL; bcr/abl;

Bio Chemical Class

Kinase

Protein Sequence

MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEISDIVQR

Open

Approved Drug

4 +

Clinical Trial Drug

7 +

Discontinued Drug

1 +

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Detailed Information

The tyrosine kinase activity of ABL1 (Abelson 1), an ABL family member, is primarily engaged in cell signal transduction. ABL1 functional domains are used in a variety of biological activities. The SRC homology (SH) domains are the most important components of its structure, with the SH3, SH2, and SH1 domains (the last being the kinase domain) being especially vital. These domains control the enzyme's autoinhibition and activation. For example, the SH3 domain keeps the enzyme in an autoinhibited state by attaching to a proline-rich region that links the SH2 and kinase domains. The SH1 kinase domain completes ABL1's tyrosine phosphorylation events, which modulate downstream signaling pathways.

Figure 1: The closed (auto-inhibited) and open (active) states of ABL kinases in Figure 1 underscore the importance of intramolecular interactions in their maintenance. Figure 1. Representation of closed and open ABL kinases to illustrate how intramolecular interactions regulate activity. (Greuber EK, et al., 2013)

Function of ABL1

The enzymatic activity of ABL1 is modulated by many molecular pathways. In its autoinhibited state, ABL1 attaches its N-terminal myristoylation site to the hydrophobic pocket at the C-terminal of the kinase domain, therefore preserving its closed conformation. Moreover, several intracellular molecules, including adaptor proteins, lipid signaling molecules, and additional kinases, can modulate ABL1's activity via interactions. Adaptor proteins such as RIN1 enhance the kinase activity of ABL1 by attaching to its SH3 and SH2 domains. Phosphatidylinositol-4,5-bisphosphate (PIP2) reduces the enzymatic activity of ABL1 when attached to it.

The nuclear localization signal (NLS) allows ABL1 to be translocated from its cytoplasmic domain to its nucleus, where it performs its tasks. Cell cycle regulation and the reaction to DNA damage are two of the many important biological activities in which ABL1 is involved within the nucleus. ABL1 phosphorylates DNA repair proteins via its kinase activity, therefore contributing to cellular responses to DNA damage. Moreover, ABL1 also influences changes in cell migration, polarity, and morphology by regulating cytoskeletal reorganization.

Role of ABL1 in Leukemia

ABL1 was first found to be an oncogene in the Abelson mouse leukemia virus. This syndrome is linked to human leukemia chromosomal translocations. Chronic myeloid leukemia (CML) is characterized by the BCR–ABL1 fusion gene. This fusion gene contains the ABL1 and BCR genes on chromosomes 9 and 22. Philadelphia chromosomal translocation (t(9;22)(q34;q11)) causes it. The fusion protein-linked tyrosine kinase's sustained activation causes neoplastic CML cells.

Because BCR–ABL1 fusion protein enzymatic activity lacks ABL1's autoinhibitory mechanism, it causes continual activation. Utilizing downstream signaling pathways RAS/RAF/MEK, JAK/STAT, and PI3K/AKT, this continuous activation stimulates leukemic cell proliferation, survival, and anti-apoptosis. Reorganizing cytoskeletons, BCR–ABL1 increases leukemic cell migration and invasion.

Figure 2: Figure 2 shows BCR-ABL1 dimerization and autophosphorylation activate several signaling pathways. Figure 2. Molecular Pathway Activation Downstream of BCR-ABL1.(Braun TP, et al., 2020)

Drugs that target ABL1 kinase activity were developed when BCR-ABL1 was shown to be a significant component of CML. Chronic myeloid leukemia patients live longer and better with imatinib. ABL1 kinase domain contacts dominate this mechanism, reducing its enzymatic activity. Dasatinib and nilotinib, second- and third-generation tyrosine kinase inhibitors address imatinib resistance and enhance therapy.

Activation Mechanisms of ABL1 in Solid Tumors

ABL1 has been widely investigated in leukemia, but new research has shown that it also plays a role in solid tumors. Solid tumors activate ABL1 by various methods, unlike leukemia, which requires chromosomal translocations. These pathways include increased ABL1 or ABL2 expression, oxidative stress, tyrosine kinase activation, chemokine receptor signaling, and negative regulatory protein inactivation.

According to studies, breast, colorectal, lung, and renal cell carcinomas exhibited higher ABL1 and ABL2 expression. ABL kinases help solid tumor cells proliferate, survive, migrate, and invade, enabling them to spread. ABL kinases regulate the cytoskeleton, which is linked to several activities. ABL kinases interact with F-actin to increase actin buildup at the cell periphery, enhancing tumor cell migration.

Despite the application of TKIs targeting ABL1 in clinical studies for solid tumors, their efficacy has been variable. Solid tumors have more complicated signaling pathways and higher TKI resistance than leukemia cells, which may explain this contradiction. In solid tumors, researchers are developing more selective ABL kinase inhibitors and patient stratification indicators to better ABL-targeted therapy.

References:

Dasgupta Y, Koptyra M, Hoser G, et al. Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases. Blood. 2016, 127(17):2131-43.
Greuber EK, Smith-Pearson P, Wang J, Pendergast AM. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer. 2013;13(8):559-571.
Braun TP, Eide CA, Druker BJ. Response and Resistance to BCR-ABL1-Targeted Therapies. Cancer Cell. 2020;37(4):530-542.

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