ABL - Tyrosine-protein kinase ABL |Elisa - Clia - Antibody - Protein

Background

ABL tyrosine-protein kinase, often referred to as ABL or c-ABL, is a member of the Abelson family of non-receptor tyrosine kinases. The ABL gene was first identified due to its involvement in the Philadelphia chromosome translocation, which is associated with chronic myeloid leukemia (CML). ABL kinases are involved in various cellular processes, including cell growth, survival, differentiation, and response to stress. It is encoded by the ABL1 gene in humans and is part of the ABL family of kinases, which also includes ABL2 (also known as Arg). Abl is involved in signaling pathways that regulate cell growth, division, adhesion, migration, and apoptosis. Abl is a cytoplasmic tyrosine kinase, meaning it phosphorylates tyrosine residues on target proteins. Abl is also involved in the regulation of the actin cytoskeleton, playing a role in cell morphology, adhesion, and motility. It interacts with various actin-binding proteins and participates in the modulation of cytoskeletal dynamics. Abl is implicated in cell cycle control. It can influence cell cycle progression by regulating the activity of key proteins involved in the cell cycle, contributing to cell division and proliferation. Abl has also Implication in Cancer: Abnormal activation or dysregulation of Abl has been associated with various cancers. The ABL1 gene can undergo chromosomal translocations, leading to the formation of fusion proteins with other genes. The most well-known example is the Philadelphia chromosome, resulting from a translocation between ABL1 and the BCR gene, which is commonly found in chronic myeloid leukemia (CML) and some acute lymphoblastic leukemias (ALL).

Protein Structure

ABL kinases have a complex structure that facilitates their diverse functions:

• SH3 Domain: Involved in protein-protein interactions, typically with proline-rich motifs.
• SH2 Domain: Binds to phosphorylated tyrosine residues, mediating interactions with other signaling proteins.
• Tyrosine Kinase Domain: Catalyzes the transfer of phosphate groups from ATP to tyrosine residues on substrate proteins, a critical activity for signaling.
• DNA-Binding Domain: Unique to ABL, allowing interaction with DNA and involvement in DNA damage response.
• Nuclear Localization Signals (NLS): Directs the transport of ABL to the nucleus, where it participates in DNA repair and transcriptional regulation.
• Nuclear Export Signals (NES): Ensures proper cellular localization by exporting ABL from the nucleus when necessary.

Classsification and Subtype

There are two main isoforms of ABL:

• ABL1: The most well-known isoform, implicated in CML and other cancers.
• ABL2 (ARG): ABL-related gene, which shares structural similarities with ABL1 but has distinct functional roles, particularly in cytoskeletal reorganization and neuronal development.

Function and Biological Significance

ABL kinases are crucial for numerous cellular processes:

1. Cell Growth and Survival: ABL regulates pathways that promote cell proliferation and prevent apoptosis, contributing to normal cellular homeostasis.
2. Cytoskeletal Dynamics: ABL influences actin cytoskeleton remodeling, affecting cell shape, motility, and adhesion.
3. DNA Damage Response: ABL's ability to interact with DNA and phosphorylate key proteins in the DNA damage response pathway is vital for maintaining genomic stability.
4. Signal Transduction: ABL modulates various signaling pathways by phosphorylating target proteins, thus influencing cellular responses to external stimuli.

Interactions

ABL interacts with numerous proteins and molecules:

1. Substrate Proteins: ABL phosphorylates a variety of substrates involved in signaling, cytoskeletal dynamics, and cell cycle regulation.
2. Adaptor Proteins: Proteins like Crk and Grb2 interact with ABL, facilitating the formation of signaling complexes.
3. DNA and DNA-Repair Proteins: ABL binds to DNA and interacts with repair proteins like RAD51, playing a role in the cellular response to DNA damage.
4. Other Kinases: ABL interacts with kinases such as Src, coordinating complex signaling networks.

Clinical Issues

Dysregulation of ABL kinase activity is associated with several diseases:

1. Chronic Myeloid Leukemia (CML): The BCR-ABL fusion protein, resulting from the Philadelphia chromosome translocation, has constitutive kinase activity, driving uncontrolled cell proliferation. Targeted therapies like imatinib (Gleevec) have been developed to inhibit BCR-ABL kinase activity.
2. Acute Lymphoblastic Leukemia (ALL): Similar to CML, BCR-ABL is also implicated in some cases of ALL, necessitating targeted kinase inhibition.
3. Solid Tumors: Abnormal ABL activity is implicated in various solid tumors, influencing cancer progression and metastasis.
4. Neurodegenerative Diseases: Given ABL’s role in neuronal signaling and cytoskeletal dynamics, its dysregulation may contribute to neurodegenerative conditions.

Summary

The ABL tyrosine-protein kinase family, including ABL1 and ABL2, plays pivotal roles in regulating cell growth, survival, cytoskeletal dynamics, and DNA damage response. Through their kinase activity and interactions with various cellular proteins and DNA, ABL kinases influence numerous signaling pathways essential for normal cellular function. Dysregulation of ABL activity is associated with significant clinical conditions, particularly various forms of leukemia and other cancers, making ABL a critical target for therapeutic intervention.