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I am learning about cell adhesion molecules (CAMs), and I know that they mediate cell-cell and cell-extracellular matrix adhesion via homophilic and heterophilic interactions. I have read that CAMs can be divided into four families based on their protein sequence and structure, including the immunoglobulin superfamily, integrins, cadherins and selectins.

I know that immunoglobulin superfamily CAMs are defined as having immunoglobulin domains in their extracellular domain.

However, I was wondering if a protein has immunoglobulin domains in the extracellular domain but a protein kinase domain in the intracellular domain (e.g. TYRO3), can it still be classified as a cell adhesion molecule belong to the immunoglobulin superfamily?

I know that the intracellular domains of CAMs can interact with cytoplasmic proteins, thus regulating intracellular signalling cascades. However, I have never read about CAMs themselves having any intrinsic enzymatic activity.

Any insights are appreciated.

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  • $\begingroup$ Not related to Ig superfamily CAMs but beta-catenin is a good example of a structural protein that also acts as a signal transducer. Many proteins have dual functions (moonlighting). $\endgroup$
    – WYSIWYG
    Feb 8, 2022 at 11:56
  • $\begingroup$ Ebnet K (2017) Junctional Adhesion Molecules (JAMs): Cell Adhesion Receptors With Pleiotropic Functions in Cell Physiology and Development." maybe just adds info to the comment above which does not answer your question? I think any cleaving or phosphorylation can be considered an "enzymatic activity". Maybe you should elaborate on "intrinsic" enzymatic activity". Premise is that CAMS like "antibodies" (immunoglobulins) "transduce" as a middle part, adhering and detaching, without any cleaving or phosphorylation? Can you give some example for: "CAMs can interact with cytoplasmic proteins"? $\endgroup$ Feb 8, 2022 at 14:53

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No, they can't.

You're right, you "...have never read about "CAMs themselves having any intrinsic enzymatic activity" - because this category does not exist. There is no explicit definition, any search to no avail. However, categorization as shown by Wikipedia, Immunoglobulin_superfamily does not suggest that categories as defined are not mutually exclusive. Hence, featuring the immunoglobulin domain cannot turn a tyrosine kinase receptor into a "cellular adhesion molecule".

Interestingly, your question seems to come up both with what those mutually exclusive categories might have in common - the immunoglobulin domain - and what - still - sets them apart: the enzymatic activity.

Some "backbone" to your question might be the question if any receptor that does not have enzymatic activity may be considered or even termed CAM, which is illustrated by the B cell receptor's popularily known presentation of antigen to T4 cells: two cells clung together by receptor, still, that is a receptor, it is no CAM. This it what makes me suggest that categorization is more formal than material.

And, what may not easily be understood in your question:

As you ask about "intrinsic" enzymatic activity you do not seem to inquire about the signaling cascade that ensues the binding of cell adhesion molecules (CAMs) to internal proteins which, themselves, may be enzymatic. In fact, cell adhesion molecules do not seem, per se, to be involved in cell signaling at all. That makes differentiating even more intricate: if some CAM as a ligand induces enzymatic activity it might be termed "enzymatic"; however, your question is not about the exclusion of receptor-like ligands from the set of CAMs, but, to the contrary, about the inclusion of proteins that - like tyrosine kinase TYR3 - are considered "receptors" into the set of CAMs (trying to be precise: you do not ask about TYR being included into CAMs but about TYR-like, i.e. receptor-like, proteins, being included in CAM). Those categories "receptors" and "CAMs" are mutually exclusive. A receptor - if defined receptor - even with no enzymatic acitivity is not a CAM.

"CAM" implies non-enzymatic activity, and the enzymatic tyrosine kinases you refer to are, in concept, opposed. This isn't trivial as you state that tyrosine kinases have the immunoglobulin-like epitope on the extracellular end. To answer your question: that doesn't change the kinase receptors being excluded from the class of CAM membrane proteins. Untrivially, what CAMS and Tyr3 (e.g.) share is their being located on or within the cell membrane. Both's function may be considered cell to cell communication.

Some reference: Rüdiger Horstkorte et al., Basic Neurochemistry (Eighth Edition), 2012https://www.sciencedirect.com/science/article/pii/B9780123749475000092

"Ig-like domains are frequently found protein domains. For example, in the human genome, there are more than 750 identified proteins with at least one Ig-like domain. Prominent examples are, in addition to the above-mentioned immunoglobulin-related molecules, receptor tyrosine kinases, co-receptors such as CD4 or CD8 and many cell adhesion molecules."

In literature, it seem's there can't be found any material arguments for delimitation.

CAMs may, in my opinion, be opposed to enzymatic proteins of the cell membrane, especially TYRO3 and other tyrosine kinase receptors, by their working principle: CAMs do not cleave as enzymes do, but adhere as specific ligands, and disolve, or do not adhere but choose. They have perfect fit or don't. They succumb to conformational change, but unlike enzymatic membrane proteines do not inflict it, by cleaving or fusing (phosphorylation). Their conformational change may even be mechanic (pulling two cell membranes tight to each other when fusing cells).

For instance Integrins (which form a category of CAMs, cp [Wikipedia, Cell adhesion molecules]:2

"Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways..." - This may lead to think of CAMs, e.g. integrin as some form of receptor, as they can bind to ligands themselves, and vice versa categorize enzymatic receptors as CAMs, as in a wider sence, CAMs, e.g. Integrin can support enzymatic receptors, TYR-receptor, moreover:

From Wikipedia, Integrin: "Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling. Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane."

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