Cell Physiology 3140A
September 18, 2013
Lecture 4 Cont’d
-There are 2 protein cores that are the major of the proteoglycan world (large
diversity of proteoglycans but 2 are major). That is perlecan and aggrecan. When
we talk about a specific proteoglycan, we name it based on the core. If the core
protein is aggrecan, that proteoglycan is called aggrecan. Aggrecan can be modified
in a number of ways. It’s the protein core that really defines the proteoglycan itself.
Perlican is highly expressed in the basal lamina and aggrecan is highly expressed in
Multiadhesive Matrix Proteins
- These proteins are like Velcro. They stick to everything in the ECM. They are like
the glue of the ECM. They bind to each other, bind to collagen, proteoglycans,
integrins and etc. These proteins are glycosylated. They are long and flexible. They
work well as those “sticky finger” grabbing other components of the matrix and cells
together. The most common multiadhesive is fibronectin. Interestingly, we have
only 1 gene of fibronectin. The special thing about that gene is that the body will
choose to splice the mRNA made in a variety of fashions. So one gene makes one
pre-mRNA and that pre-mRNA will be spliced alternatively. So some of the
fibronectin pre-mRNAs will remain their full length, some introns removed, some
with more exons and etc. This is called isoforms. One gene makes many isoforms.
Therefore the body can very nicely can pick the kinds of fibronectin it likes to have
and splice it they way it want to. There are 2 forms of fibronectin. One is soluble and
insoluble. The soluble form can float around in the blood plasma and associated
with RBCs. Insoluble fibronectin associated in the ECM of the rest of the tissues in
the body. Fibronectin is important for a lot of things. It is essential for wound
healing. It is involved in the blood clotting process by becoming soluble or insoluble.
When there is a cut, soluble fibronectin that floats in blood plasma will go to the site
of the wound and help with the blood clot formation. Then fibronectin can morph
into the insoluble form. The way it morphs into the insoluble form is that cells start
attaching to it due to the stickiness of the fibronectin. Cells pull the fibronectin, as
that happens; it releases a fold in that molecule causing the fibronectin to become
insoluble. Just by stretching of the fibronectin molecule, it becomes insoluble, and it
now functions in the matrix to get the tissue to pull back together. When the skin is
coming back together, it will help pull cells and the matrix and close the wound. - Laminin is another multiadhesive matrix protein with similar functions. It sticks
to everything and keeps the matrix together.
Integrins Signal Between Cells and Their Environment
- Intergrins are a type of cell adhesion molecule (specifically a transmembrane
protein) that interacts in the cytoplasm of the cell and connects the inside of the cell
to the outside (ECM). When integrins are functioning, we have an alpha subunit and
a beta subunit. So these are 2 separate integrin proteins. So you are either made
from an alpha gene or a beta gene. We always have an alpha and a beta that come
together. Every alpha and beta will bind to a different component of the ECM. There
are 18 alpha subunits and 8 beta subunits (18 alpha genes and 8 beta genes). There
are lots of different combinations that can be made. Only 24 pairs or combinations
have been found in vivo. Integrins have 2 types of signaling, which are: outside-in-
signaling and inside-out-signaling. Outside- in-signaling is the cell has touched
the matrix (integrin has interacted with a component in the matrix). This causes a
cytoplasmic change causing some type of signal transduction event. Thus there is
some kind of internal change that causes the signaling cascade and changes the way
the inside of the cell to function. Inside-out-signaling is when the
integrins(cytoplasmic side) will be activated and it will change the extracellular
matrix domain so it can/can’t interact with the matrix. The cell can control if the
integrin can interact with the matrix component or not. This is called bi-directional
Samples of Known Integrin Heterodimers
- a1b1: It’s ligands are collagen (mainly type I and IV). It’s cell-type distribution is
in multiple cells. It interacts extracellularly with collagen type I and IV.
- a3b1: It interacts with laminins(multiadhesive matrix proteins). It is a
widespread type of integrin (in multiple cells).
*Note b1 common subunit and is apart of a lot of subtypes identified
-a5b1: It’s ligands are fibronectin. It’s expressed in fibroblast. Fibroblasts are
involved in cell wound healing and migration. If you have a mutation in a5, then you
would have a fibroblast phenotype. This means that fibroblast will be affected.
-a6b4: It interacts with laminins. Epithelial cells express it. There are epithelial
cells in many places (skin, lining of gastrointestinal tract, lungs). This integrin is
important for connecting these cells to Laminin (multi adhesive matrix protein).
*Note: There are no integrins found that bind to proteoglycans in matrix.
Case Study: Epidermolysis bullosa
- This is a skin condition that results from a mutation in the a6 subunit of the
integrin. It is a epithelial specific integrin and it interacts with laminins. This
mutation results in skin blistering and skin fragility. If you cannot connect skin cells
to the matrix the body made, if you rub on an individuals skin that has that problem
with the defective integrin, it creates blistering and skin breaking. Cell Physiology – Cell – Cell Interactions
Properties affecting cell-cell adhesion strength
- 1) Binding affinity: 2 cells come together and they’ll both express a protein that
will cause an interaction between the 2. Depending on how well the proteins like
each other will affect how tightly the cells will be bound to each other.
- 2) Spatial distribution: If you have more proteins in the cell membrane that come
together with other proteins, so spatially they are really close together, and that will
increase the strength of those 2 cells interacting with each other. Conversely, if you
have cell adhesion molecules that are far apart or less of them then the interaction
will be we