Structural Biochemistry/Cell Signaling Pathways/Juxtacrine Signaling

Juxtacrine Signaling
In juxtacrine interactions, proteins from the inducing cell interact with receptor proteins of adjacent responding cells. The inducer does not diffuse from the cell producing it. There are three types of juxtacrine interactions:

1)	A protein on one cell binds to the corresponding receptor on the cell right next to it. 2)	A receptor on one cell binds to its ligand on the extracellular matrix given off by another cell. 3)	The signal is transmitted from the cytoplasm of a cell through the cytoplasm to an adjacent cell.

Juxtocrine signaling is a type of intercellular communication that is transmitted by oligosaccharide, lipid or protein components of a cell membrane. Many juxtocrine signals affect the emitting cell or the adjacent cells nearby. A juxtocrine signal occurs between neighboring cells that have extensive patches of closely opposed plasma membranes linked by transmembrane channels known as connexons. Unlike other types of cell signaling, like paracrine and endocrine, juxtacrine signaling requires physical contact between the two cells involved. There are three types of signaling modes of juxtacrine interactions:

The Notch Pathway

The Extracellular matrix

Gap Junctions

The Notch Pathway

Notch proteins are activated by cells that express the Delta, Jagged or Serrate proteins in their cell membranes and is present in most multicellular organisms. A Notch protein extends through the cell membrane and has an external compartment exposed to the outsides, which is where it contacts Delta, Jagged or Serrate proteins that are protruding out from an adjacent cell. When attached to one of these ligands, Notch proteins undergo a conformational change that enables it to be cut by a protease. The cleaved portion enters the nucleus and binds to an inactive transcription factor of the CSL family. When bound to the Notch protein, the CSL transcription factors activate their target genes.

There exists four different notch receptors in mammals: NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein.

Discovered in 1917 by Thomas Hunt Morgan, the Notch gene was noticed in the wingblades of a strain of the fruit fly Drosophila melanogaster. Further analysis was conducted as the molecular analysis and sequencing took place in the 1980s.

The signaling pathway of a Notch protein is important for cell-cell communication which takes place during embryonic life and in adults. It plays a role in:

1.) Neural function and development

2.) Cardiac valve homeostasis along with other repercussions in disorders involving the cardiovascular system

3.) Cell lineage specification of the endocrine and exocrine pancreas

4.) Regulation of cell-fate in mammary glands at several development stages

5.) stabilization of arterial endothelial fate and angiogenesis (the growth of new blood vessels from pre-existing vessels).

6.) regulation of crucial cell communication ev ents between endocardium and myocardium during the formation of the primordial valve and the ventricular development and differentiation.

7.) influencing of binary fate decisions of cells- between secretory and absorptive lineages in the stomach

8.)expansion of the hematopoietic stem cell compartment during bone development and participation in the osteoblastic lineage inferring potential therapeutic role for Notch in bone regeneration and osteoporosis

Disease involving Notch signalling include: T-ALL (T-cell acute lymphoblastic leukemia), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalophy), Multiple Sclerosis (MS), Tetralogy of Fallot, Alagile syndrome as well as other disease.

The Extracellular Matrix as a Source of Critical Developmental Signals The extracellular matrix consists of macromolecules secreted by cells into their immediate environment. Macromolecules form a region of noncellular material in the regions between cells. The extracellular matrix is made up of collagen, proteoglycans and a variety of specialized glycoprotein molecules such as fibronectin and laminin. These two glycoprotein molecules are responsible for organizing the matrix and cells into an ordered structure.



Fibronectin is a large glycoprotein dimer synthesized by numerous cell types. It’s function is to serve as a general adhesive molecule linking cells to one another and to other substrates such as collagen and proteoglycans. It has several distinct binding sites and their interaction with appropriate molecules result in proper alignment of cells with extracellular matrix.

Laminin along with Type IV Collagen is a major component of a type of extracellular matrix called basal lamina. Laminin plays a role in assembling the extracellular matrix, promoting cell adhesion and growth, changing cell shape and permitting cell migration. The ability of a cell to bind to Laminin and Fibronectin depends on its expression of a cell membrane receptor for the cell-binding site of these large molecules. Fibronectin receptor complexes bind fibronectin on the outside of the cell and bind the cytoskeleton proteins on the inside of the cell. Fibronectin receptor complexes span the cell membrane and unite two types of matrices. On the outside, it binds to fibronectin of the extracellular matrix, while on the inside it serves as an anchorage site for actin microfilaments that move the cell. These receptor proteins are known as integrins because they integrate extracellular and intracellular scaffolds, allowing them to work together. On the extracellular side, integrins bind to an arginine-lysine-aspartate (RGD) sequence, while on the cytoplasmic side, integrins bind to talin and alpha actin, two proteins that connect to actin filaments. The dual binding enables cells to move by contracting actin microfilaments against a fixed extracellular matrix. The binding of integrins to the extracellular matrix can stimulate RTK-Ras pathway. When an integrin on a cell membrane of one cell binds to the fibronection or collagen secreted by a neighboring cell, integrins can activate tyrosine kinase cascades through an adaptor protein-like complex that connects the integrins to a Ras G protein. Direct Transmission of Signals through Gap Junctions Gap junctions, also called nexus, are made up of connexin proteins and serve as communication channels between adjacent cells. Six identical connexins in the membrane group make up one connexon (hemichannel) and two connexons makes up one gap junction. The channel complex of one cell connects to the channel complex of another cell, enabling cytoplasm of both cells to be joined. When two identical connexons come together to form a gap junction, it is called a homotypic gap junction. When there is one homomeric connexon and one heteromeric connexon that come together or two heteromeric connexons join it is called a heterotypic gap junction. Properties of gap junctions include:

1.) They allow for direct electrical communication between cells

2.) They allow for chemical communication between cells through transmission of small second messengers

3.) They allow molecules smaller than 1,000 Daltons to pass through

4.) Ensure that molecules and currents passing through gap junction do not leak into the intracellular space.



Example
Below is an example of the autocrine versus juxtacrine signaling modes. In step 1 of the autocrine signaling, the signaling is regulated by the removal of the prepro-extension from the membrane-anchored ligand, following by its controlled release from the membrane in step 2. Orientation restrictions are responsible for the release requirement. On the other hand, in step 1 of the juxtacrine signaling, the prepro-extension release is required, following by the binding to the auxiliary molecule on a neighboring cell in step 2. Furthermore, autocrin ligands bind to the cell that produced them, while, juxtacrine ligands bind to a neighboring cell.