Cell Junction and Cytoskeleton-related signaling

Types of cell junction

There are three major types of cell junctions: tight junctions, gap junctions, and adherens junctions, each with distinct molecular composition and signaling roles.

Additional anchoring junctions such as adherens junctions, desmosomes, hemidesmosomes, and focal adhesions physically connect cells to each other or to the extracellular matrix, providing mechanical support and coordinating cytoskeletal organization. By linking cytoskeletal filaments to neighboring cells or the extracellular matrix, these junctions support tissue integrity, morphogenesis, and mechanotransduction.

• Tight junction signaling – Tight junctions seal the space between epithelial and endothelial cells, regulating paracellular permeability and maintaining polarity. They are composed of claudins, occludin, junctional adhesion molecules, and scaffold proteins such as ZO-1. Beyond their barrier role, tight junctions act as signaling hubs within the cell junction network that regulate polarity and proliferation.
• Gap junction signaling – Gap junctions form direct cytoplasmic channels between cells, enabling passage of ions, metabolites, and signaling molecules. Connexin-based channels allow tissues to synchronize electrical activity, metabolic states, and responses to stress. Their regulation by phosphorylation, calcium, and voltage ensures precise control of communication.
• Adherens junction signaling – Adherens junctions provide strong adhesive links between cells through cadherin–catenin complexes that connect to the actin cytoskeleton. They are critical for maintaining epithelial integrity, coordinating morphogenesis, and regulating signaling pathways such as Wnt/β-catenin. Their dynamic remodeling also enables tissue flexibility during development and wound repair.

Together, these cell junctions coordinate intercellular adhesion, mechanical stability, and cytoskeletal signaling to maintain tissue organization, support mechanotransduction, and enable adaptive responses during development and stress.

Integrin signaling in Cell–Matrix Adhesion

Also important for cytoskeletal integrity, integrin signaling links cells to the extracellular matrix, coordinating adhesion with cytoskeletal organization.

Integrin signaling is also critical for cytoskeletal integrity, linking cells to the extracellular matrix and coordinating cell–matrix adhesion with cytoskeletal organization.

Integrin receptors and Focal Adhesions

Integrins are a large family of heterodimeric transmembrane receptors that are crucial for mediating cell-extracellular matrix (ECM) and cell-cell interactions. Composed of membrane spanning alpha and beta subunits that mix and match to regulate different processes, integrins are activated by both “inside-out” and “outside-in” signals.

β-integrins generally have a short cytoplasmic tail that is accessible within the cytoplasm. Intracellular signals promote clustering and binding of intracellular adaptor proteins like Talin1 and Kindlin to the β-integrin tail. Binding triggers a conformational switch that enables the adaptors to interact with F-actin and is essential for integrin-dependent attachment and formation of focal adhesions – adhesion complexes that provide an anchor to the ECM. At the same time, conformational changes within the receptor itself result in “inside-out” increased affinity for ECM ligands.

Engagement of integrin receptors with extracellular ligands triggers “outside-in” signaling and activates formation of complexes of scaffold/adaptor proteins including paxillin, FAK and ILK that promote assembly of a variety of signaling components. Signaling through these scaffold/adaptor complexes at focal adhesions regulates several key cellular processes including growth factor-induced mitogenic signals, cell survival, cell proliferation and migration, cell locomotion and regulation of cell cycle.

Paxillin and FAK as Central Integrin Signaling Adaptors

Paxillin is an important adaptor protein that acts as a hub that connects structural and signaling components of the cell, coordinating downstream signaling through multiple other proteins. While it can be difficult to tease apart the exact recruitment steps, FAK (focal adhesion kinase), also known as PTK2, is one of the main partners of paxillin signaling. FAK recruits and forms a complex with Src tyrosine kinase which acts through JNK, MAPK and PI3K/Akt pathways among others to influence cytoskeletal organization, cell proliferation and more.

Paxillin additionally influences cell tension through its interaction with GIT1 (G protein-coupled receptor kinase-interacting protein 1) which complexes with guanine nucleotide exchange factors to target CDC42 and Rac/Rho.

ILK as a Scaffold in Integrin-Dependent Signaling Pathways

Intricately linked with paxillin and FAK is a third scaffold/adaptor protein, ILK (integrin-linked kinase), that also plays a role in downstream PI3K/Akt, CDC42 and Rac/Rho signaling. Originally identified as a serine-threonine kinase, it is now believed that ILK may be a pseudo-kinase, which like paxillin, acts only as a scaffold protein.

Consequences of disrupted cell junction and cytoskeleton signaling

Integrity of junctional and cytoskeletal signaling is essential for normal tissue function. Disruption of cell junction can have wide-ranging consequences:

• Barrier dysfunction: Loss of tight junction integrity contributes to inflammatory diseases, neurodegeneration, and pathogen invasion.
• Impaired communication: Defective gap junction signaling leads to arrhythmias, neuropathies, cataracts, and deafness.
• Loss of adhesion and polarity: Breakdown of adherens junctions facilitates epithelial–mesenchymal transition (EMT), promoting cancer progression and metastasis.
• Aberrant migration and survival: Dysregulated integrin signaling disrupts cell survival pathways, impairs wound healing, and enhances invasive behavior in tumors.
• Cytoskeletal instability: Altered actin dynamics compromise tissue architecture and mechanosensing, leading to developmental defects and degenerative disease.

References

1. Li S, Sampson C, Liu C, Piao H, Liu H. Integrin signaling in cancer: Bidirectional mechanisms and therapeutic opportunities. Cell Commun Signal. 2023;21(1):266.
2. Ripamonti M, Wehrle-Haller B, de Curtis I. Paxillin: A hub for mechano-transduction from the β3 integrin-talin-kindlin axis. Front Cell Dev Biol. 2022;10:852016.
3. Górska A, Mazur AJ. Integrin-linked kinase (ILK): The known vs. the unknown and perspectives. Cell Mol Life Sci. 2022;79(2):100.