Junctional adhesion molecule

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Junctional Adhesion Molecule
PDB 1nbq EBI.jpg
Crystallographic structure of junctional adhesion molecules linked together
Identifiers
SymbolJAM
Membranome Immunoglobulin set domain V set domain

A junctional adhesion molecule (JAM) is a protein that is a member of the immunoglobulin superfamily, [1] [2] and is expressed in a variety of different tissues, such as leukocytes, platelets, and epithelial and endothelial cells. [2] They have been shown to regulate signal complex assembly on both their cytoplasmic and extracellular domains through interaction with scaffolding that contains a PDZ domain and adjacent cell's receptors, respectively. [3] JAMs adhere to adjacent cells through interactions with integrins LFA-1 and Mac-1, which are contained in leukocyte β2 and α4β1, which is contained in β1. JAMs have many influences on leukocyte-endothelial cell interactions, which are primarily moderated by the integrins discussed above. [4] They interact in their cytoplasmic domain with scaffold proteins that contain a PDZ domain, which are common protein interaction modules that target short amino acid sequences at the C-terminus of proteins, to form tight junctions in both epithelial and endothelial cells as polarity is gained in the cell. [3]

Contents

Structure

JAMs are usually around 40 kDa in size. [5] Based on crystallographic studies conducted with recombinant extracellular mouse JAMs (rsJAM) and human JAMs (hJAM), it has been shown that JAM consists of immunoglobulin-like V-set domain followed by a second immunoglobulin domain that are linked together by a short linker sequence. The linker makes extensive hydrogen bonds to both domains, and the side chain of one of the main linker residues, Leu128, is commonly embedded in a hydrophobic cleft between each immunoglobulin-like domain. [6] Two JAM molecules contain N-terminal domains that react in a highly complementary fashion due to prolific ionic and hydrophobic interactions. These two molecules form U-shaped dimers and salt bridges are then formed by a R(V,I,L)E motif. [6] This motif has been proven to be important in dimer formation and is common among different types of JAMs. It commonly consists of Arg58-Val59-Glu60 located on the N-terminus and can dissociate into monomers based on the conditions of the solution it is exposed to. This motif has been shown to be present in many common variants of JAMs, including rsJAM, hJAM, JAM-1, JAM-2, and JAM-3. [7]

Types

Three major JAM molecules interact with various molecules and receptors within the body:

Tight junctions are formed from action of different JAM proteins working in conjunction. Many of these JAM proteins will be localized in these junctions. Cellular tight junction-it.svg
Tight junctions are formed from action of different JAM proteins working in conjunction. Many of these JAM proteins will be localized in these junctions.

JAM-1

JAM-1 was the first of the junctional adhesion molecules to be discovered, and is located in the tight junctions of both epithelial and endothelia l cells. [8] JAM-1interacts with cells in a homophilic manner in order to preserve the structure of the junction while moderating its permeability. It can also interact with receptors as a heterophilic structure by acting as a ligand for LFA-1 and facilitating leukocyte transmigration. [8] JAM-1 also plays a significant role in many different cellular functions, including being both a reovirus receptor and a platelet receptor. [8]

JAM-2

Like JAM-1, JAM-2 also is a member of the immunoglobulin superfamily. [9] JAM-2 localization is moderated by serine phosphorylation at tight junctions as the molecule adheres to other tight junction proteins like PAR-3 and ZO-1. JAM-2 has been shown to interact with these proteins, primarily through the PDZ1 domain, and also through the PDZ3 domain. [10] JAM-2 has also shown to act as a ligand for many immune cells, and plays a role in lymphocyte attraction to specific organs. [10]

JAM-3

JAM-3 functions similarly to JAM-2 as it is localized around the tight junctions of epithelial and endothelial cells, but has been shown to be unable to adhere to leukocytes in the manner that other JAMs can. [11] Mutations of JAM-3 introns have been shown to lead to brain hemorrhages and development of cataracts. [11] Like JAM-2, JAM-3 has been shown associate with tight junction proteins like PAR-3 and ZO-1. JAM-3 has also been shown to interact with PARD3 (partitioning defective 3 homolog).[ citation needed ]

Function

JAMs serve many different functions within the cell:

Cell motility

JAMs play a critical role in the regulation of cell movement in multiple different cell types, such as epithelial, endothelial, leukocyte, and germ cells. [10] JAM-1 regulates motility in epithelial cells by moderating expression of β1 integrin protein downstream of Rap1. JAM-1 has been shown to be able to cause cell adhesion, spreading and movement along β1 ligands, like collagen IV and fibronectin. [3] JAM-1 also acts to moderate migration of vitronectin in endothelial cells. Vitronectin is a ligand for integrins αvβ3 and αvβ5, which exhibit selective cooperativity with bFGF and VEGF in the activation of the MAPK pathway. JAM-1 and JAM-3 allow leukocytes to migrate into connective tissue by freeing polymorphonuclear leukocytes from entrapment in endothelial cells and basement membranes. [3] In the absence of JAM-1, these leukocytes cannot moderate β1 integrin endocytosis, and cannot be effectively expressed on the surface of the cell (which is essential for motility). [11]

Cell polarity

JAM-1 and JAM-3 have significant roles in regulating cell polarity through their interactions with cell polarity proteins. [5] JAM-1, JAM-2, and JAM-3 all interact with PAR-3 to influence cell polarity. PAR-3 is a significant factor in a cell's polarity-regulating complex, and regulates polarity in different cell types in many different organisms. [12] All components of the PAR complex are required for tight junction formation between cells, but premature adherens junctions can form without PAR complex components being present. [3] However, these junctions cannot efficiently develop into mature epithelial cell junctions. JAM-3 has also shown to affect cell polarity in spermatids by regulating the localization of cytosolic polarity. [10]

Cell Proliferation

In order to preserve homeostasis of adult tissue, aged cells must be replaced with new cells at varying frequency, depending on the organ. Some organs that require high rates of cellular turnover are the small intestine and the colon. JAM-1 has been shown to regulate the proliferation of cells in the colon. [8] In JAM-1 deficient mice, it has been found that the amount of proliferating cells in the colon greatly increased due to the increased proliferation of TA cells. JAM-1 acts to suppress cell proliferation, which is performed by restricting Akt activity. [8] Recent studies have also pointed to JAM-1 preserving structural integrity of tissues more so than regulating cell number.

Role in physiological processes

JAMs play a significant role in many diverse physiological processes within the human body, including:

Tight junction formation

Tight junctions serve to provide most of the function for the barrier that is present on epithelial cell surfaces. Tight junctions feature the localization of both JAM-1 and JAM-3, and JAM-3 is localized exclusively at tight junctions. [3] The role of JAM-1 in tight junction biology is to function through mediation partly due to the localization of the Par-αPKC complex at adherens junctions during junction creation. [3] Once the tight junction is formed, many JAM-1 proteins are present, many of which are now phosphorylated at Ser285. [3] JAM-1 also regulates the activity of many different claudins within different epithelial cells. [7]

Angiogenesis

Angiogenesis is the generation of blood vessels from old blood vessels. Studies have shown that proteins found in tight junctions serve as intermediaries that moderate angiogenic signaling pathways. JAM-1 induces proliferation of endothelial cells, which begins the process of angiogenesis. [13] An analysis of JAM-1 showed a correlation between JAM-1 activity and FGF2-induced angiogenesis in both cancerous proliferation or vascular repair. [13]

Male fertility

JAM-3 has been shown to be a primary regulator of the development of spermatids as well as the rest of the male reproductive system. Within the Sertoli cells of the male reproductive system, JAM-3 interacts with JAM-2 to influence the polarity of both round and elongated spermatids. [12] JAM-1 and JAM-2 are also present in and contribute to the polarity of the blood-testis barrier. Studies have also shown that inactivation of JAM-3 has been shown to significantly impede fertility by blocking male germ cell development and proliferation. [3]

Related Research Articles

<span class="mw-page-title-main">Cell adhesion</span> Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

<span class="mw-page-title-main">Cell junction</span> Multiprotein complex that forms a point of contact or adhesion in animal cells

Cell junctions or junctional complexes, are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together.

Protease-activated receptors(PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, fibroblasts, immune cells, myocytes, neurons, and tissues that line the gastrointestinal tract.

<span class="mw-page-title-main">Tight junction</span> Structure preventing inter-cell leakage

Tight junctions, also known as occluding junctions or zonulae occludentes, are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epithelial cells. They also play a critical role maintaining the structure and permeability of endothelial cells. Tight junctions may also serve as leaky pathways by forming selective channels for small cations, anions, or water. The corresponding junctions that occur in invertebrates are septate junctions.

<span class="mw-page-title-main">ICAM-1</span> Mammalian protein found in Homo sapiens

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

<span class="mw-page-title-main">VCAM-1</span> Protein-coding gene in the species Homo sapiens

Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the VCAM1 gene. VCAM-1 functions as a cell adhesion molecule.

<span class="mw-page-title-main">Leukocyte extravasation</span>

Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

<span class="mw-page-title-main">Tight junction protein 1</span> Protein found in humans

Zonula occludens-1 ZO-1, also known as Tight junction protein-1 is a 220-kD peripheral membrane protein that is encoded by the TJP1 gene in humans. It belongs to the family of zonula occludens proteins, which are tight junction-associated proteins and of which, ZO-1 is the first to be cloned. It was first isolated in 1986 by Stevenson and Goodenough using a monoclonal antibody raised in rodent liver to recognise a 225-kD polypeptide in whole liver homogenates and in tight junction-enriched membrane fractions. It has a role as a scaffold protein which cross-links and anchors Tight Junction (TJ) strand proteins, which are fibril-like structures within the lipid bilayer, to the actin cytoskeleton.

<span class="mw-page-title-main">Afadin</span> Protein-coding gene in the species Homo sapiens

Afadin is a protein that in humans is encoded by the AFDN gene.

<span class="mw-page-title-main">F11 receptor</span> Protein-coding gene in the species Homo sapiens

Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321.

<span class="mw-page-title-main">Poliovirus receptor-related 1</span> Protein-coding gene in the species Homo sapiens

Poliovirus receptor-related 1 (PVRL1), also known as nectin-1 and CD111 (formerly herpesvirus entry mediator C, HVEC) is a human protein of the immunoglobulin superfamily (IgSF), also considered a member of the nectins. It is a membrane protein with three extracellular immunoglobulin domains, a single transmembrane helix and a cytoplasmic tail. The protein can mediate Ca2+-independent cellular adhesion further characterizing it as IgSF cell adhesion molecule (IgSF CAM).

<span class="mw-page-title-main">PARD3</span> Protein-coding gene in the species Homo sapiens

Partitioning defective 3 homolog is a protein that in humans is encoded by the PARD3 gene.

<span class="mw-page-title-main">JAM3</span> Protein-coding gene in the species Homo sapiens

Junctional adhesion molecule C is a protein that in humans is encoded by the JAM3 gene.

<span class="mw-page-title-main">JAM2</span> Protein-coding gene in the species Homo sapiens

Junctional adhesion molecule B is a protein that in humans is encoded by the JAM2 gene. JAM2 has also been designated as CD322.

JAML or Junctional Adhesion Molecule-Like, or AMICA1 is a JAM transmembrane protein family member. It is composed of two extracellular immunoglobulin-like domains, a membrane-spanning region, and a cytoplasmic tail involved in activation signaling. A known ligand of JAML is Coxsackie virus and Adenovirus Receptor which has been shown to localize to the tight junctions of epithelial cells.

Collagen receptors are membrane proteins that bind the extracellular matrix protein collagen, the most abundant protein in mammals. They control mainly cell proliferation, migration and adhesion, coagulation cascade activation and they affect ECM structure by regulation of MMP.

Epithelial polarity is one example of the cell polarity that is a fundamental feature of many types of cells. Epithelial cells feature distinct 'apical', 'lateral' and 'basal' plasma membrane domains. Epithelial cells connect to one another via their lateral membranes to form epithelial sheets that line cavities and surfaces throughout the animal body. Each plasma membrane domain has a distinct protein composition, giving them distinct properties and allowing directional transport of molecules across the epithelial sheet. How epithelial cells generate and maintain polarity remains unclear, but certain molecules have been found to play a key role.

Cell–cell interaction refers to the direct interactions between cell surfaces that play a crucial role in the development and function of multicellular organisms. These interactions allow cells to communicate with each other in response to changes in their microenvironment. This ability to send and receive signals is essential for the survival of the cell. Interactions between cells can be stable such as those made through cell junctions. These junctions are involved in the communication and organization of cells within a particular tissue. Others are transient or temporary such as those between cells of the immune system or the interactions involved in tissue inflammation. These types of intercellular interactions are distinguished from other types such as those between cells and the extracellular matrix. The loss of communication between cells can result in uncontrollable cell growth and cancer.

Tight junction proteins are molecules situated at the tight junctions of epithelial, endothelial and myelinated cells. This multiprotein junctional complex has a regulatory function in passage of ions, water and solutes through the paracellular pathway. It can also coordinate the motion of lipids and proteins between the apical and basolateral surfaces of the plasma membrane. Thereby tight junction conducts signaling molecules, that influence the differentiation, proliferation and polarity of cells. So tight junction plays a key role in maintenance of osmotic balance and trans-cellular transport of tissue specific molecules. Nowadays is known more than 40 different proteins, that are involved in these selective TJ channels.

References

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  2. 1 2 Ebnet K, Suzuki A, Ohno S, Vestweber D (January 2004). "Junctional adhesion molecules (JAMs): more molecules with dual functions?". Journal of Cell Science. 117 (Pt 1): 19–29. doi:10.1242/jcs.00930. PMID   14657270.
  3. 1 2 3 4 5 6 7 8 9 Ebnet K (October 2017). "Junctional Adhesion Molecules (JAMs): Cell Adhesion Receptors With Pleiotropic Functions in Cell Physiology and Development". Physiological Reviews. 97 (4): 1529–1554. doi:10.1152/physrev.00004.2017. PMID   28931565. S2CID   10846721.
  4. ↑ Lee HJ, Zheng JJ (May 2010). "PDZ domains and their binding partners: structure, specificity, and modification". Cell Communication and Signaling. 8 (1): 8. doi:10.1186/1478-811X-8-8. PMC   2891790 . PMID   20509869.
  5. 1 2 Bauer HC, Traweger A, Bauer H (2004-01-01). "Proteins of the Tight Junction in the Blood-Brain Barrier". In HS, Westman J (eds.). 1 - Proteins of the Tight Junction in the Blood-Brain Barrier. pp. 1–10. doi:10.1016/b978-012639011-7/50005-x. ISBN   978-0-12-639011-7.{{cite book}}: |work= ignored (help)
  6. 1 2 Kostrewa D, Brockhaus M, D'Arcy A, Dale GE, Nelboeck P, Schmid G, et al. (August 2001). "X-ray structure of junctional adhesion molecule: structural basis for homophilic adhesion via a novel dimerization motif". The EMBO Journal. 20 (16): 4391–8. doi:10.1093/emboj/20.16.4391. PMC   125582 . PMID   11500366.
  7. 1 2 Prota AE, Campbell JA, Schelling P, Forrest JC, Watson MJ, Peters TR, et al. (April 2003). "Crystal structure of human junctional adhesion molecule 1: implications for reovirus binding". Proceedings of the National Academy of Sciences of the United States of America. 100 (9): 5366–71. Bibcode:2003PNAS..100.5366P. doi: 10.1073/pnas.0937718100 . PMC   404559 . PMID   12697893.
  8. 1 2 3 4 5 Naik UP, Eckfeld K (2003). "Junctional adhesion molecule 1 (JAM-1)". Journal of Biological Regulators and Homeostatic Agents. 17 (4): 341–7. PMID   15065765.
  9. ↑ "JAM2 junctional adhesion molecule 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-11-29.
  10. 1 2 3 4 Ebnet K, Aurrand-Lions M, Kuhn A, Kiefer F, Butz S, Zander K, et al. (October 2003). "The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity". Journal of Cell Science. 116 (Pt 19): 3879–91. doi: 10.1242/jcs.00704 . PMID   12953056.
  11. 1 2 3 "JAM3 junctional adhesion molecule 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-11-29.
  12. 1 2 Rehder D, Iden S, Nasdala I, Wegener J, Brickwedde MK, Vestweber D, Ebnet K (October 2006). "Junctional adhesion molecule-a participates in the formation of apico-basal polarity through different domains". Experimental Cell Research. 312 (17): 3389–403. doi:10.1016/j.yexcr.2006.07.004. PMID   16919624.
  13. 1 2 Naik TU, Naik MU, Naik UP (January 2008). "Junctional adhesion molecules in angiogenesis". Frontiers in Bioscience. 13 (13): 258–62. doi: 10.2741/2676 . PMID   17981544. S2CID   11562413.
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