Unit 3-cell cell interactions

Cellular interactions- By, K. P. Komal, GSC, CTA.
By, K. P. Komal, Assistant professor, Govt. Science College, Chitradurga
2016-17
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Lecture notes in Cellular Biochemistry
Topic: Cellular Interactions
By,
Mrs. K. P. Komal
Assistant professor in Biochemistry
Government Science College, Chitradurga
Karnataka. 577501

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Extracellular matrix:
• In biology, the extracellular matrix (ECM) is a collection of extracellular molecules secreted
by cells that provides structural and biochemical support to the surrounding cells.
• Because multicellularity evolved independently in different multicellular lineages, the
composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell
communication and differentiation are common functions of the ECM.
• The animal extracellular matrix includes the interstitial matrix and the basement membrane.
• Interstitial matrix is present between various animal cells (i.e., in the intercellular spaces). Gels
of polysaccharides and fibrous proteins fill the interstitial space and act as a compression
buffer against the stress placed on the ECM.
• Basement membranes are sheet-like depositions of ECM on which various epithelial cells rest.
• Each type of connective tissue in animals has a type of ECM: collagen fibers and bone
mineral comprise the ECM of bone tissue; reticular fibers and ground substance comprise the
ECM of loose connective tissue; and blood plasma is the ECM of blood.
• The plant ECM includes cell wall components, like cellulose, in addition to more complex
signaling molecules.
• Some single-celled organisms adopt multicellular biofilms in which the cells are embedded in
an ECM composed primarily of extracellular polymeric substances (EPS).
Role and importance
• Due to its diverse nature and composition, the ECM can serve many functions, such as providing
support, segregating tissues from one another, and regulating intercellular communication.
• The extracellular matrix regulates a cell's dynamic behavior.
• In addition, it sequesters a wide range of cellular growth factors and acts as a local store for
them.
• Changes in physiological conditions can trigger protease activities that cause local release of
such stores. This allows the rapid and local growth factor-mediated activation of cellular
functions without de novo synthesis.
• Formation of the extracellular matrix is essential for processes like growth, wound healing,
and fibrosis.
• An understanding of ECM structure and composition also helps in comprehending the complex
dynamics of tumor invasion and metastasis in cancer biology as metastasis often involves the
destruction of extracellular matrix by enzymes such as serine proteases, threonine proteases,
and matrix metalloproteinases.

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• The stiffness and elasticity of the ECM has important implications in cell migration, gene
expression, and differentiation.
• Cells actively sense ECM rigidity and migrate preferentially towards stiffer surfaces in a
phenomenon called durotaxis.
• They also detect elasticity and adjust their gene expression accordingly which has increasingly
become a subject of research because of its impact on differentiation and cancer progression.
Molecular components
• Components of the ECM are produced intracellularly by resident cells and secreted into the
ECM via exocytosis.
• Once secreted, they then aggregate with the existing matrix.
• The ECM is composed of an interlocking mesh of fibrous proteins and
glycosaminoglycans (GAGs).
Proteoglycans
• Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists
of a "core protein" with one or more covalently attached glycosaminoglycan (GAG)
chain(s). The point of attachment is a serine (Ser) residue to which the glycosaminoglycan is
joined through a tetrasaccharide bridge (e.g. chondroitin sulfate-GlcA-Gal-Gal-Xyl-PROTEIN).

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The Ser residue is generally in the sequence -Ser-Gly-X-Gly- (where X can be any amino acid
residue but Proline), although not every protein with this sequence has an attached
glycosaminoglycan. The chains are long, linear carbohydrate polymers that are negatively
charged under physiological conditions due to the occurrence of sulfate and uronic acid groups.
Proteoglycans occur in the connective tissue.
Synthesis
The protein component of proteoglycans is synthesized by ribosomes and translocated into the lumen
of the rough endoplasmic reticulum. Glycosylation of the proteoglycan occurs in the Golgi apparatus in
multiple enzymatic steps. First a special link tetrasaccharide is attached to a serine side chain on the
core protein to serve as a primer for polysaccharide growth. Then sugars are added one at a time by
glycosyl transferase. The completed proteoglycan is then exported in secretory vesicles to the
extracellular matrix of the tissue.
Function
• Proteoglycans are a major component of the animal extracellular matrix, the "filler" substance
existing between cells in an organism. Here they form large complexes, both to other
proteoglycans, to hyaluronan, and to fibrous matrix proteins (such as collagen).
• They are also involved in binding cations (such as sodium, potassium and calcium) andwater,
and also regulating the movement of molecules through the matrix.
• Evidence also shows they can affect the activity and stability of proteins and signalling
molecules within the matrix.
• Individual functions of proteoglycans can be attributed to either the protein core or the
attached GAG chain and serve as lubricants.
Glycosaminoglycans (GAGs) are carbohydrate polymers and are usually attached to extracellular
matrix proteins to form proteoglycans (hyaluronic acid is a notable exception, see below).
Proteoglycans have a net negative charge that attracts positively charged sodium ions (Na+), which
attracts water molecules via osmosis, keeping the ECM and resident cells hydrated. Proteoglycans may
also help to trap and store growth factors within the ECM.
There are the different types of proteoglycan found within the extracellular matrix. They are,

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Heparan sulfate
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as
a proteoglycan (PG) in which two or three HS chains are attached in close proximity to cell surface or
ECM proteins. It is in this form that HS binds to a variety of protein ligands and regulates a wide
variety of biological activities, including developmental processes, angiogenesis, blood coagulation,
and tumor metastasis.
In the extracellular matrix, especially basement membranes, the multi-domain proteins perlecan,
agrin, and collagen XVIII are the main proteins to which heparan sulfate is attached.
Chondroitin sulfate
Chondroitin sulfates contribute to the tensile strength of cartilage, tendons, ligaments, and walls of
the aorta. They have also been known to affect neuroplasticity.
Keratan sulfate
Keratan sulfates have a variable sulfate content and, unlike many other GAGs, do not contain uronic
acid. They are present in the cornea, cartilage, bones, and the horns of animals.
Non-proteoglycan polysaccharide
Hyaluronic acid
• Hyaluronic acid (or "hyaluronan") is a polysaccharide consisting of alternating residues of D-
glucuronic acid and N-acetylglucosamine, and unlike other GAGs, is not found as a
proteoglycan.
• Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression
by providing a counteracting turgor (swelling) force by absorbing significant amounts of water.
• Hyaluronic acid is thus found in abundance in the ECM of load-bearing joints. It is also a chief
component of the interstitial gel.
• Hyaluronic acid is found on the inner surface of the cell membrane and is translocated out of
the cell during biosynthesis.
• Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic
development, healing processes, inflammation, and tumor development. It interacts with a
specific transmembrane receptor, CD44.
Fibers
Collagen
• Collagens are the most abundant protein in the ECM. In fact, collagen is the most abundant
protein in the human body and accounts for 90% of bone matrix protein content.
• Collagen is the main structural protein in the extracellular space in the various connective
tissues in animal bodies.

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• As the main component of connective tissue, it is the most abundant protein in
mammals, making up from 25% to 35% of the whole-body protein content. Depending upon
the degree of mineralization, collagen tissues may be rigid (bone), compliant (tendon), or have
a gradient from rigid to compliant (cartilage).
• Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such
as tendons, ligaments and skin. It is also abundant in corneas, cartilage, bones, blood vessels,
the gut, inter vertebral discs and the dentin in teeth.
• In muscle tissue, it serves as a major component of the endomysium.
• Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of
strong, tendinous muscles. The fibroblast is the most common cell that creates collagen.
• Gelatin, which is used in food and industry, is collagen that has been
irreversibly hydrolyzed. Collagen also has many medical uses in treating complications of the
bones and skin.
• Collagens are present in the ECM as fibrillar proteins and give structural support to resident
cells. Collagen is exocytosed in precursor form (procollagen), which is then cleaved by
procollagen proteases to allow extracellular assembly. Disorders such as Ehlers Danlos
Syndrome, osteogenesis imperfecta, and epidermolysis bullosa are linked with genetic
defects in collagen-encoding genes.
• The collagen can be divided into several families according to the types of structure they form:
1. Fibrillar (Type I, II, III, V, XI)
2. Facit (Type IX, XII, XIV)
3. Short chain (Type VIII, X)
4. Basement membrane (Type IV)
5. Other (Type VI, VII, XIII)
So far, 28 types of collagen have been identified and described. They can also be divided into several
groups according to the structure they form:
➢ Fibrillar (Type I, II, III, V, XI)
➢ Non-fibrillar
✓ FACIT (Fibril Associated Collagens with Interrupted Triple Helices) (Type IX, XII,
XIV, XVI, XIX)
✓ Short chain (Type VIII, X)
✓ Basement membrane (Type IV)
✓ Multiplexin (Multiple Triple Helix domains with Interruptions) (Type XV, XVIII)
✓ MACIT (Membrane Associated Collagens with Interrupted Triple Helices) (Type XIII,
XVII)

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✓ Other (Type VI, VII)
The five most common types are:
✓ Type I: skin, tendon, vascular ligature, organs, bone (main component of the organic part of
bone)
✓ Type II: cartilage (main collagenous component of cartilage)
✓ Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
✓ Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
✓ Type V: cell surfaces, hair and placenta
Synthesis
First, a three-dimensional stranded structure is assembled, with the amino acids glycine and
proline as its principal components. This is not yet collagen but its precursor, procollagen. Procollagen
is then modified by the addition of hydroxyl groups to the amino acids proline and lysine. This step is
important for later glycosylation and the formation of the triple helix structure of collagen. The
hydroxylase enzymes that perform these reactions require Vitamin C as a cofactor, and a deficiency in
this vitamin results in impaired collagen synthesis and the resulting disease scurvy. These
hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase and lysyl-
hydroxylase. Vitamin C also serves with them in inducing these reactions. In this service, one
molecule of vitamin C is destroyed for each H replaced by OH. The synthesis of collagen occurs inside
and outside of the cell.
1. Transcription of mRNA: About 34 genes are associated with collagen formation, each coding
for a specific mRNA sequence, and typically have the "COL" prefix. The beginning of collagen
synthesis begins with turning on genes which are associated with the formation of a particular
alpha peptide (typically alpha 1, 2 or 3).
2. Pre-pro-peptide formation: Once the final mRNA exits from the cell nucleus and enters into
the cytoplasm, it links with the ribosomal subunits and the process of translation occurs. The
early/first part of the new peptide is known as the signal sequence. The signal sequence on
the N-terminal of the peptide is recognized by a signal recognition particle on the endoplasmic
reticulum, which will be responsible for directing the pre-pro-peptide into the endoplasmic
reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the
endoplasmic reticulum for post-translational processing. It is now known as pre-pro-collagen.
3. Pre-pro-peptide to pro-collagen: Three modifications of the pre-pro-peptide occur leading to
the formation of the alpha peptide:
1. The signal peptide on the N-terminal is dissolved, and the molecule is now known
as propeptide (not procollagen).
2. Hydroxylation of lysines and prolines on propeptide by the enzymes 'prolyl hydroxylase'
and 'lysyl hydroxylase' (to produce hydroxyproline and hydroxylysine) occurs to aid
cross-linking of the alpha peptides. This enzymatic step requires vitamin C as a

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cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser
triple helix (which is formed by three alpha peptides).
3. Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl
groups that were placed onto lysines, but not on prolines.
4. Once these modifications have taken place, three of the hydroxylated and glycosylated
propeptides twist into a triple helix forming procollagen. Procollagen still has unwound
ends, which will be later trimmed. At this point, the procollagen is packaged into a
transfer vesicle destined for the Golgi apparatus.
4. Golgi apparatus modification: In the Golgi apparatus, the procollagen goes through one last
post-translational modification before being secreted out of the cell. In this step,
oligosaccharides (not monosaccharides as in step 3) are added, and then the procollagen is
packaged into a secretory vesicle destined for the extracellular space.
5. Formation of tropocollagen: Once outside the cell, membrane bound enzymes known as
'collagen peptidases', remove the "loose ends" of the procollagen molecule. What is left is
known as tropocollagen. Defects in this step produce one of the many collagenopathies known
as Ehlers-Danlos syndrome. This step is absent when synthesizing type III, a type of fibrilar
collagen.
6. Formation of the collagen fibril: 'Lysyl oxidase', an extracellular enzyme, produces the final
step in the collagen synthesis pathway. This enzyme acts on lysines and hydroxylysines
producing aldehyde groups, which will eventually undergo covalent bonding between
tropocollagen molecules. This polymer of tropocollogen is known as a collagen fibril.
Action of Lysine oxidase

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Amino acids
Collagen has an unusual amino acid composition and sequence:
✓ Glycine is found at almost every third residue.
✓ Proline makes up about 17% of collagen.
✓ Collagen contains two uncommon derivative amino acids not directly inserted
during translation. These amino acids are found at specific locations relative to glycine and
are modified post-translationally by different enzymes, both of which require vitamin C as
acofactor.
✓ Hydroxyproline derived from proline
✓ Hydroxylysine derived from lysine - depending on the type of collagen, varying numbers of
hydroxylysines are glycosylated (mostly having disaccharides attached).
Cortisol stimulates degradation of (skin) collagen into amino acids.
Collagen I formation
Most collagen forms in a similar manner, but the following process is typical for type I:
1. Inside the cell
1. Two types of alpha chains are formed during translation on ribosomes along the rough
endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains
(known as preprocollagen) have registration peptides on each end and a signal peptide.
2. Polypeptide chains are released into the lumen of the RER.
3. Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha
chains.
4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is
dependent on ascorbic acid (vitamin C) as a cofactor.
5. Glycosylation of specific hydroxylysine residues occurs.
6. Triple alpha helical structure is formed inside the endoplasmic reticulum from two
alpha-1 chains and one alpha-2 chain.
7. Procollagen is shipped to the Golgi apparatus, where it is packaged and secreted
by exocytosis.
2. Outside the cell
1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
2. Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol
reaction) by lysyl oxidase which links hydroxylysine and lysine residues. Multiple
collagen fibrils form into collagen fibers.
3. Collagen may be attached to cell membranes via several types of protein,
including fibronectin and integrin.

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Elastin
Elastins, in contrast to collagens, give elasticity to tissues, allowing them to stretch when
needed and then return to their original state.
This is useful in blood vessels, the lungs, inskin, and the ligamentum nuchae, and these tissues
contain high amounts of elastins.
Elastins are synthesized by fibroblasts and smooth muscle cells.
Elastins are highly insoluble, and tropoelastins are secreted inside a chaperone molecule, which
releases the precursor molecule upon contact with a fiber of mature elastin.
Tropoelastins are then deaminated to become incorporated into the elastin strand.
Disorders such as cutis laxa and Williams syndrome are associated with deficient or absent
elastin fibers in the ECM.
Other
Fibronectin
Fibronectins are glycoproteins that connect cells with collagen fibers in the ECM, allowing cells
to move through the ECM.
Fibronectins bind collagen and cell-surface integrins, causing a reorganization of the
cell's cytoskeleton to facilitate cell movement.
Fibronectins are secreted by cells in an unfolded, inactive form. Binding to integrins unfolds
fibronectin molecules, allowing them to form dimers so that they can function properly.
Fibronectins also help at the site of tissue injury by binding to platelets during blood
clottingand facilitating cell movement to the affected area during wound healing.
Laminin
Laminins are proteins found in the basal laminae of virtually all animals. Rather than forming collagen-
like fibers, laminins form networks of web-like structures that resist tensile forces in the basal lamina.
They also assist in cell adhesion. Laminins bind other ECM components such as collagens
and nidogens.
Mechanical properties of the ECM
Stiffness and elasticity
The ECM can exist in varying degrees of stiffness and elasticity, from soft brain tissues to hard bone
tissues. Cells can sense the mechanical properties of their environment by applying forces and
measuring the resulting backlash. This plays an important role because it helps regulate many
important cellular processes including cellular contraction, cell migration, cell proliferation,
differentiation and cell death (apoptosis).

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Durotaxis
Stiffness and elasticity also guide cell migration, this process is called durotaxis. The term was coined
by Lo CM and colleagues when they discovered the tendency of single cells to migrate up rigidity
gradients (towards more stiff substrates) and has been extensively studied since. The molecular
mechanisms behind durotaxis are thought to exist primarily in the focal adhesion, a large protein
complex that acts as the primary site of contact between the cell and the ECM. This complex contains
many proteins that are essential to durotaxis including structural anchoring proteins (integrins) and
signaling proteins (adhesion kinase (FAK), talin, vinculin, paxillin, α-actinin, GTPases etc.) which cause
changes in cell shape and actomyosin contractility. These changes are thought to
cause cytoskeletal rearrangements in order to facilitate directional migration.
Cell adhesion to the ECM
Many cells bind to components of the extracellular matrix. Cell adhesion can occur in two ways;
by focal adhesions, connecting the ECM to actin filaments of the cell, and hemidesmosomes, connecting
the ECM to intermediate filaments such as keratin. This cell-to-ECM adhesion is regulated by specific
cell-surface cellular adhesion molecules(CAM) known as integrins. Integrins are cell-surface proteins
that bind cells to ECM structures, such as fibronectin and laminin, and also to integrin proteins on the
surface of other cells.
Fibronectins bind to ECM macromolecules and facilitate their binding to transmembrane integrins.
The attachment of fibronectin to the extracellular domain initiates intracellular signalling pathways as
well as association with the cellular cytoskeleton via a set of adaptor molecules such as actin.
Cell–cell interaction
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.

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Stable interactions
Stable cell-cell interactions are required for cell adhesion within a tissue and controlling the
shape and function of cells.
These stable interactions involve cell junctions which are multiprotein complexes that provide
contact between neighboring cells.
Cell junctions allow for the preservation and proper functioning of epithelial cell sheets.
These junctions are also important in the organization of tissues where cells of one type can
only adhere to cells of the same tissue rather than to a different tissue.
Tight junctions
Tight junctions, also known as occluding junctions or zonulae occludentes (singular ,
zonula occludens), are the closely associated areas of two cells whose membranes join
together forming a virtually impermeable barrier to fluid. It is a type of junctional
complex present only in vertebrates. The corresponding junctions that occur in invertebrates
are septate junctions.
Tight junctions are multi-protein complexes that hold cells of a same tissue together and
prevent movement of water and water-soluble molecules between cells.
In epithelial cells, they function also to separate the extracellular fluid surrounding their apical
and basolateral membranes.
These junctions exist as a continuous band located just below the apical surface between the
membranes of neighboring epithelial cells.
The tight junctions on adjacent cells line up so as to produce a seal between different tissues
and body cavities. For example, the apical surface of gastrointestinal epithelial cells serve as a
selective permeable barrier that separates the external environment from the body.
The permeability of these junctions is dependent on a variety of factors including protein
makeup of that junction, tissue type and signaling from the cells.

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Tight junctions are made up of many different proteins. The four main transmembrane proteins
are occludin, claudin, junctional adhesion molecules (JAMs) and tricellulins.
The extracellular domains of these proteins form the tight junction barrier by making
homophilic (between proteins of the same kind) and heterophilic interactions (between
different types of proteins) with the protein domains on adjacent cells. Their cytoplasmic
domains interact with the cell cytoskeleton to anchor them.
Anchoring junctions
Of the three types of anchoring junctions, only two are involved in cell-cell interactions: adherens
junctions and desmosomes. Both are found in many types of cells. Adjacent epithelial cells are
connected by adherens junctions on their lateral membranes. They are located just below tight
junctions. Their function is to give shape and tension to cells and tissues and they are also the site of
cell-cell signaling. Adherens junctions are made of cell adhesion molecules from the cadherin family.
There are over 100 types of cadherins, corresponding to the many different types of cells and tissues
with varying anchoring needs. The most common are E-, N- and P-cadherins. In the adherens junctions
of epithelial cells, E-cadherin is the most abundant.
Desmosomes also provide strength and durability to cells and tissues and are located just below
adherens junctions. They are sites of adhesion and do not encircle the cell. They are made of two
specialized cadherins, desmoglein and desmocollin. These proteins have extracellular domains that
interact with each other on adjacent cells. On the cytoplasmic side, plakins form plaques which anchor
the desmosomes to intermediate filaments composed of keratin proteins. Desmosomes also play a role
in cell-cell signaling.
Gap junctions
Gap junctions are the main site of cell-cell signaling or communication that allow small
molecules to diffuse between adjacent cells.
In vertebrates, gap junctions are composed of transmembrane proteins called connexins.
They form hexagonal pores or channels through which ions, sugars, and other small molecules
can pass.
Each pore is made of 12 connexin molecules; 6 form a hemichannel on one cell membrane and
interact with a hemichannel on an adjacent cell membrane.
The permeability of these junctions is regulated by many factors including pH and Ca2+
concentration.

Unit 3-cell cell interactions

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