ROR - receptor tyrosine kinase like orphan receptor | Elisa - Clia - Antibody - Protein

Background

The Receptor Tyrosine Kinase-Like Orphan Receptors (RORs) are a distinct family of receptor tyrosine kinases (RTKs) that play pivotal roles in developmental processes and cellular signaling pathways. RORs are evolutionarily conserved proteins that were initially identified through their homology with other RTKs but were termed "orphan receptors" due to the initial lack of identified ligands. The ROR family includes two members in humans: ROR1 and ROR2. Both receptors have been implicated in various biological processes, including embryonic development, cell polarity, and organogenesis. Recent research has expanded the understanding of RORs' involvement in disease states, particularly in cancer and skeletal disorders.

Protein Structure

ROR proteins are composed of several distinct domains that contribute to their function:

1. Extracellular Domain: The extracellular region of RORs includes an immunoglobulin (Ig)-like domain, a cysteine-rich domain (CRD), and a kringle domain. The CRD is similar to that found in Frizzled receptors and is involved in binding Wnt ligands.
2. Transmembrane Domain: This single-pass transmembrane domain anchors the receptor in the cell membrane.
3. Intracellular Domain: The intracellular portion contains a tyrosine kinase domain, which is characteristic of RTKs, although the kinase activity of RORs is generally lower than that of other RTKs. Additionally, the intracellular region includes proline-rich sequences and serine/threonine-rich regions that mediate interactions with intracellular signaling molecules.

Classification and Subtypes

RORs are classified within the receptor tyrosine kinase family but are grouped separately due to their unique structural features and functional properties. The two main subtypes are:

1. ROR1: Primarily expressed during embryonic development and has limited expression in adult tissues. ROR1 has been extensively studied in the context of chronic lymphocytic leukemia (CLL) and other cancers.
2. ROR2: Expressed in various tissues during development, ROR2 plays a crucial role in skeletal and organ development. Mutations in ROR2 are associated with skeletal disorders such as Robinow syndrome.

Function and Biological Significance

RORs are key players in the non-canonical Wnt signaling pathway, which is involved in regulating cell movement and polarity rather than cell fate determination. The primary functions of RORs include:

• Developmental Roles: ROR1 and ROR2 are critical for proper embryonic development. They influence cell migration, polarity, and organogenesis. For instance, ROR2 is essential for skeletal development, with its absence leading to severe developmental abnormalities.
• Cell Signaling: RORs interact with Wnt5a, a ligand that activates non-canonical Wnt signaling. This interaction modulates cytoskeletal dynamics and cellular polarity, impacting processes like cell migration and invasion.
• Cancer: Overexpression of ROR1 and ROR2 has been linked to various cancers. ROR1 is notably overexpressed in CLL and certain solid tumors, where it promotes cell survival and proliferation. ROR2 is implicated in tumor progression and metastasis through its role in cell motility and invasion.

Clinical Issues

The clinical implications of RORs are primarily related to their roles in cancer and genetic disorders:

• Cancer Therapy: ROR1 is a promising therapeutic target in oncology. Monoclonal antibodies and small molecule inhibitors targeting ROR1 are being developed to treat ROR1-expressing cancers. Clinical trials are underway to evaluate the efficacy of these therapies in CLL and other malignancies.
• Genetic Disorders: Mutations in ROR2 are linked to autosomal recessive Robinow syndrome and brachydactyly type B, characterized by skeletal abnormalities. Understanding the molecular mechanisms of these mutations helps in diagnosing and potentially developing therapeutic interventions for these conditions.

Summary

ROR1 and ROR2 are integral to various developmental and pathological processes. Their involvement in non-canonical Wnt signaling and the regulation of cell movement, polarity, and proliferation underscores their biological significance. While ROR1 is predominantly associated with oncogenesis, particularly in hematologic malignancies, ROR2's role is critical in skeletal development and associated disorders. The therapeutic targeting of RORs, especially ROR1, holds promise for advancing cancer treatment, with ongoing research aiming to translate these findings into clinical applications. The exploration of RORs continues to unravel their complex functions and potential as biomarkers and therapeutic targets in various diseases.