CRKL-Crk-like protein | Elisa - Clia - Antibody - Protein

Background

CRKL (Crk-like protein) is an adaptor protein that plays a crucial role in intracellular signal transduction pathways. It is a member of the CRK family of adaptor proteins, which also includes CRK. CRKL is involved in various cellular processes, including cell growth, adhesion, migration, and differentiation. It functions primarily by linking receptor tyrosine kinases (RTKs) and other signaling proteins to downstream effectors, facilitating the assembly of multi-protein signaling complexes. CRKL is widely expressed in different tissues, with particularly high expression levels in hematopoietic cells. Its involvement in multiple signaling pathways underscores its importance in both normal cellular functions and disease processes.

Protein Structure

CRKL’s structure is characterized by specific domains that facilitate its role as an adaptor protein:

• SH2 (Src Homology 2) Domain: This domain binds to phosphorylated tyrosine residues on target proteins, allowing CRKL to be recruited to activated RTKs and other phosphorylated signaling proteins.
• Two SH3 (Src Homology 3) Domains: These domains interact with proline-rich sequences on other proteins. The N-terminal SH3 domain typically binds to proline-rich sequences on other adapter proteins or kinases, while the C-terminal SH3 domain regulates CRKL's interaction with its partners.
• Linker Regions: These regions connect the SH2 and SH3 domains, providing flexibility and enabling proper spatial arrangement for interaction with other signaling molecules.

Classification and Subtypes

CRKL is classified as an adaptor protein within the CRK family, which includes:

• CRK: The primary member involved in various signaling pathways.
• CRKL: A closely related homolog with similar functions and structure, often compensating for or complementing CRK's roles in cellular signaling.

Function and Biological Significance

CRKL is involved in multiple critical cellular functions:

• Signal Transduction: CRKL acts as a bridge connecting activated RTKs or other phosphorylated signaling molecules to downstream effectors, thus propagating cellular signals.
• Cell Migration and Adhesion: By interacting with focal adhesion proteins and small GTPases, CRKL plays a role in cytoskeletal reorganization and cell movement. This is essential for processes such as wound healing, immune response, and cancer metastasis.
• Cell Growth and Survival: CRKL participates in pathways that regulate cell proliferation and survival, including the Ras-MAPK and PI3K-AKT signaling pathways.
• Differentiation: CRKL is involved in pathways that regulate cellular differentiation, particularly in hematopoietic cells.

Clinical Issues

Alterations in CRKL function or expression are associated with several diseases:

• Cancer: Overexpression or dysregulation of CRKL is linked to various cancers, including chronic myeloid leukemia (CML) and lung cancer. CRKL contributes to oncogenesis by promoting cell proliferation, survival, and metastasis.
• Chronic Myeloid Leukemia (CML): CRKL is a substrate of the BCR-ABL fusion protein, which is the hallmark of CML. Phosphorylation of CRKL by BCR-ABL leads to aberrant signaling pathways that drive the pathogenesis of CML.
• Developmental Disorders: Genetic mutations in CRKL have been implicated in congenital abnormalities, such as DiGeorge syndrome, which is characterized by defects in the development of the heart, thymus, and parathyroid glands.
• Fibrosis: CRKL has been implicated in the development of fibrosis in various organs, including the lungs and liver, where it mediates signaling pathways that promote tissue remodeling and fibrosis.

Summary

CRKL is a multifunctional adaptor protein essential for various signal transduction pathways that regulate cell growth, adhesion, migration, and differentiation. Its structure includes an SH2 domain and two SH3 domains, enabling it to mediate interactions between phosphorylated proteins and other signaling molecules. By assembling signaling complexes, CRKL propagates intracellular signals crucial for numerous cellular functions. Dysregulation of CRKL is associated with diseases such as cancer, CML, developmental disorders, and fibrosis. Understanding CRKL's role in these processes is vital for developing therapeutic strategies targeting its signaling pathways in various diseases.