JAM3 Human

What is JAM3 and what is its structural composition?

JAM3, also known as JAM-C, is a member of the JAM subfamily that includes six main members: JAM1, JAM2, JAM3, JAM4, ESAM, and CAR. These proteins are selectively expressed in various human tissues and are implicated in physiological and pathological functions through cell adhesion involving homophilic and heterophilic interactions . Full-length human JAM3 is an approximately 43 kDa protein with two extracellular immunoglobulin-like domains, a transmembrane domain, and a C-terminal PDZ-binding motif . Its structure enables it to participate in tight junction formation and maintenance across multiple tissue types.

Where is JAM3 expressed in the human body?

Human JAM3 is expressed at high levels in the brain, kidney, and placenta . It is also present on the surface of platelets and abundantly expressed in intestinal epithelial cells . Interestingly, the tissue distribution of JAM3 differs significantly between humans and mice, with Jam3 (the mouse ortholog) reported to be absent in vasculature of the adult mouse brain and showing only low-level expression in developing and adult mouse brains . This species-specific difference underscores the importance of human-focused studies when investigating JAM3 function.

What are the primary functions of JAM3 in human physiology?

JAM3 serves multiple critical functions in human physiology:

• Barrier function maintenance in epithelial and endothelial layers

• Leukocyte migration regulation

• Platelet activation

• Angiogenesis (blood vessel formation)

• Cell adhesion through specialized junctions

Research indicates JAM3 may have a unique function in cerebrovascular endothelium, as disruption of JAM3 function has been shown to affect permeability of human dermal microvascular endothelial cells and human umbilical-vein endothelial cells .

How are JAM3 mutations associated with human diseases?

Homozygous mutations in the JAM3 gene have been associated with significant pathological conditions affecting multiple organ systems. Clinical manifestations include:

Three out of four affected individuals who had abdominal imaging were found to have abnormalities in one or both kidneys . While the presence of exaggerated deep-tendon reflexes suggests severe defects in nerve conduction are unlikely, mild conduction defects cannot be ruled out without electrophysiological studies .

What is JAM3's role in cancer biology?

JAM3 has emerged as a potential tumor suppressor gene, particularly in colorectal cancer (CRC). Research demonstrates that:

• JAM3 may function as a novel tumor suppressor gene with epigenetic reduction in CRC

• JAM3 protein levels are downregulated in 75% (18/24) of CRC cases

• JAM3 mRNA is markedly downregulated in CRC plasma samples compared to normal samples

• JAM3 protein and mRNA expression levels are significantly decreased in multiple CRC cell lines

Additionally, over-expression of JAM3 has been shown to improve tight junctions and recover an epithelial phenotype in lung squamous cell carcinoma cells, while its expression is downregulated in gastric adenocarcinoma .

What experimental designs are most effective for studying JAM3 function?

When designing experiments to study JAM3 function, researchers should consider the following approaches:

• True experimental designs: These follow specific characteristics as described by Campbell (1957) and include:

  • Random assignment of subjects

  • Manipulation of the independent variable

  • Control over extraneous variables

• Human subject considerations: For studies involving human tissues or participants, researchers must comply with regulations regarding the treatment of people in research activities (such as 45 CFR 46). These studies require ethical review and may be classified as:

  • Exempt human subjects research

  • Human subjects research subject to expedited review

  • Human subjects research subject to full IRB review

• Animal models: Engineered mice deficient for Jam3 have been reported to show:

  • Growth retardation

  • Increased susceptibility to pneumonia

  • Nuclear cataracts

  • Defects in peripheral nerve conduction

  • Abnormalities in spermatid differentiation and granulocyte homeostasis

When translating findings between species, researchers must account for significant differences in JAM3 expression patterns between humans and mice .

How can JAM3 methylation status be effectively analyzed?

JAM3 methylation analysis requires systematic approaches for accurate assessment:

• Study design considerations:

  • JAM3 methylation status can be treated as both a continuous variable and a categorical variable

  • Statistical methods should assess differences in JAM3 methylation status by age, sex, tumor stage, and tumor location

  • Student's t-test or rank-sum test may be appropriate depending on data distribution

• Analytical methods:

  • Receiver-operating characteristic (ROC) curves can evaluate the diagnostic performance of JAM3 methylation

  • Correlation analyses can examine relationships between methylation and expression levels (e.g., an inverse correlation has been observed with r = –0.3575, P = 0.0323)

  • Molecular interaction networks involving JAM3 and related proteins like TJP1 can be generated using specialized databases

What approaches should be used when handling contradictory data in JAM3 research?

Contradictory findings are common in biomedical research and require systematic evaluation:

• Structured classification of contradiction patterns:

  • Consider using a notation system with parameters (α, β, θ), where:

    • α represents the number of interdependent items

    • β represents the number of contradictory dependencies defined by domain experts

    • θ represents the minimal number of required Boolean rules

• Methodological considerations:

  • Evaluate whether contradictions arise from differing methodological approaches

  • Consider biological context variations across studies

  • Analyze whether the minimum number of Boolean rules might be significantly lower than the number of described contradictions

• Systematic resolution framework:

  • A structured classification of contradiction checks allows scoping of different contradiction patterns across multiple domains

  • This approach can effectively support the implementation of a generalized contradiction assessment framework

For example, some studies show that disruption of JAM3 function leads to a decrease in permeability of human dermal microvascular endothelial cells, while others suggest different effects in other contexts .

How can JAM3 be utilized as a biomarker for disease detection?

JAM3 shows promising potential as a biomarker, particularly for colorectal cancer:

• Diagnostic performance:

  • JAM3 mRNA detection in plasma samples has demonstrated an area under the curve (AUC) of 0.8611, indicating good diagnostic accuracy

  • JAM3 protein levels are downregulated in 75% of CRC cases, especially in tissues with hypermethylation of the JAM3 promoter

• Non-invasive detection:

  • JAM3 can be used as a potential noninvasive biomarker for CRC diagnosis

  • JAM3 mRNA can be detected in plasma samples, providing a less invasive alternative to tissue biopsies

• Methylation biomarkers:

  • DNA methylation of the JAM3 promoter correlates with decreased expression and could serve as an epigenetic biomarker

What methodological considerations are important when analyzing JAM3 expression in clinical samples?

When analyzing JAM3 expression in clinical samples, researchers should consider:

• Multiple detection methods:

  • Quantitative mRNA analysis through RT-PCR

  • Protein detection through western blot analysis

  • Immunohistochemistry using tissue microarrays (TMA)

• Reference standards:

  • Compare JAM3 expression in disease tissues against appropriate controls

  • For CRC studies, compare against paired normal tissues and non-cancerous cell lines like NCM460

• Integrated analysis:

  • Correlate JAM3 expression with methylation status

  • Combine mRNA and protein expression data for comprehensive assessment

  • Consider JAM3 expression in relation to clinical parameters and patient outcomes

What are the key knowledge gaps in JAM3 human research?

Despite significant progress, several knowledge gaps remain in JAM3 research:

• Developmental roles:

  • Studies of additional patients with mutations in JAM3 would help determine its potential role in human cardiac and renal development

• Tissue-specific functions:

  • Further research is needed to clarify JAM3's unique functions in cerebrovascular endothelium versus other tissue types

• Therapeutic targeting:

  • Investigation into whether restoring JAM3 expression could have therapeutic benefits in cancers where it is downregulated

• Molecular mechanisms:

  • More detailed understanding of how JAM3 functions in tight junction formation and maintenance at the molecular level

How can human-centered design principles be applied to JAM3 research?

Incorporating human-centered design principles can enhance JAM3 research:

• Stakeholder engagement:

  • Engage patients, community members, care providers, and researchers in collaborative problem-solving

  • Use abductive reasoning to find new opportunities and explore what could be

• Key practices:

  • Build empathy with affected populations

  • Think by doing through iterative research approaches

  • Make things visual through clear data representation

  • Combine divergent and convergent approaches

  • Foster collaboration among stakeholders

• Research "Jams":

  • Consider implementing "Jam" activities that empower people to express thoughts and ideas

  • Use generative techniques to access deeper knowledge beyond what participants can easily communicate