CRABP2

Cellular Retinoic Acid Binding Protein 2 (CRABP2) plays a critical role in retinoic acid (RA) signaling and regulates cell differentiation, growth, immune function, and metabolism. 

Its dysregulation has been implicated in various diseases, including cancer, autoimmune disorders, and developmental syndromes, making it a key focus for research on biomarkers and targeted therapies.

What is CRABP2?

The CRABP2 (Cellular Retinoic Acid Binding Protein 2) gene is located on chromosome 1 and encodes a member of the intracellular lipid-binding protein family. 

This small cytosolic protein is involved in retinoic acid (RA) signaling, acting as a carrier that transports all-trans retinoic acid (ATRA) to nuclear retinoic acid receptors (RARs). 

Once inside the nucleus, RA binds to RARs and retinoid X receptors (RXRs), activating gene transcription responsible for regulating cell differentiation, growth, apoptosis, and immune function.

CRABP2 is distinct from CRABP1, another retinoic acid-binding protein, due to its stronger affinity for RA and direct involvement in nuclear receptor-mediated gene expression. 

While CRABP1 may act as a buffer for RA in the cytoplasm, CRABP2 specifically enhances RA's transcriptional effects by ensuring its targeted delivery to nuclear receptors. 

CRABP2 is specifically expressed in the skin, ovary, breast, and testis in adults, highlighting its role in development, tissue maintenance, and disease progression.

Function of CRABP2

CRABP2 is essential to RA-mediated signaling, which impacts various physiological processes, including:

Embryonic Development

CRABP2 regulates neural crest differentiation, limb formation, and organogenesis by controlling RA distribution during early development.

Cell Differentiation and Proliferation

CRABP2 is also involved in cell differentiation and proliferation. For example, RA is essential for epithelial tissue maintenance, influencing processes such as keratinocyte differentiation in the skin.

Immune Regulation

CRABP2 is induced in activated T cells, balancing regulatory T cells (Tregs) and pro-inflammatory Th17 cells, playing a potential role in autoimmune disease. CRABP2 also has non-genomic functions in the cytoplasm that enhance inflammatory cytokine expression.

Metabolism and Lipid Regulation

Recent findings suggest CRABP2 may be linked to lipid metabolism, with evidence indicating its association with LDL cholesterol levels.

Clinical Implications of CRABP2 Mutations

CRABP2 mutations can be associated with:

Cancer Progression and Therapeutic Resistance

CRABP2 is abnormally expressed in several cancer types, influencing tumor behavior in a context-dependent manner:

Glioblastoma Multiforme (GBM)

In glioblastoma (GBM), CRABP2 is misplaced in the cytoplasm, trapping retinoic acid (RA) and blocking its ability to activate nuclear receptors. This drives tumor growth, worsens prognosis, and increases the risk of recurrence. 

Lowering CRABP2 levels in GBM cells may slow tumor growth and restore sensitivity to RA, suggesting CRABP2 could be a target for RA-based treatments.

Breast Cancer

CRABP2 has a dual role in estrogen receptor (ER)-dependent breast cancer. CRABP2 acts as a tumor suppressor in ER+ breast cancer, reducing cell invasion and metastasis.

However, in ER– breast cancer, CRABP2 promotes tumor progression, leading to increased metastasis.

Therefore, CRABP2 may be used as a prognostic indicator in breast cancer. Low CRABP2 levels in ER+ breast cancer correlate with worse outcomes, while high CRABP2 expression in ER− breast cancer is linked to poor prognosis.

Ovarian Cancer and Chemotherapy Resistance

CRABP2 is highly expressed in drug-resistant ovarian cancer cells, promoting metabolic adaptation through HIF1α upregulation and increased ATP production.

Targeting CRABP2 or HIF1α could improve chemotherapy response, highlighting CRABP2’s role in ovarian cancer treatment resistance.

Endometrial Cancer

High CRABP2 expression in endometrial cancer (EC) is linked to advanced disease stage, high tumor grade, and poor survival outcomes, particularly in aggressive subtypes like serous EC. 

Other Cancers

Dysregulation of CRABP2 has been reported in pancreatic cancer, neuroblastoma, Wilms tumor, head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer (NSCLC), suggesting broader oncogenic roles.

Skeletal Dysplasia and Developmental Disorders: Marshall-Smith Syndrome (MSS)

Marshall-Smith Syndrome (MSS) is a rare genetic disorder marked by accelerated bone growth, skeletal abnormalities, craniofacial malformations, and neurodevelopmental delays. 

Affected individuals often experience low muscle tone (hypotonia), cerebellar underdevelopment, and coordination difficulties, along with airway obstruction due to a small jaw and nasal passage defects, which can lead to severe respiratory distress requiring tracheostomy. 

Feeding difficulties, poor weight gain, and kidney issues like hydronephrosis further complicate management. 

MSS is linked to mutations in the NFIX transcription factor, which increase CRABP2 expression, potentially amplifying retinoic acid (RA) signaling. This dysregulation may drive bone malformations, reduced bone mineral density, and altered brain development; 

It also suggests that RA-modulating therapies could be a potential treatment avenue for MSS-related skeletal and neurological complications.

Autoimmune and Inflammatory Diseases

CRABP2 is highly expressed in activated CD4+ T cells and influences the balance between regulatory T cells (Tregs) and inflammatory Th17 cells, which may be seen in conditions such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).

Increased CRABP2 expression in autoimmune diseases correlates with excessive inflammation, as seen in biopsies from autoimmune patients.

Who Should Get CRABP2 Tested?

CRABP2 is not commonly tested in clinical settings; instead, it is primarily used in research settings. For example, CRABP2 genetic mutations may be tested in cancer or developmental biology research. 

Test Procedure and Interpretation

The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for CRABP2 genetic testing are considered to be without mutations that can alter the activity of the CRABP2 proteins.

Clinical Implications of Positive CRABP2 Mutations

The clinical implications of a positive CRABP2 mutation test result will vary by individual, although CRABP2 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various symptoms and/or known or suspected cancer.

Patients or practitioners with questions about the clinical implications of CRABP2 mutations should seek further assessment with a genetic counselor or expert. 

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