KANK2 at focal adhesion regulates their maintenance and dynamics, while at fibrillar adhesions it influences cell migration via microtubule-dependent mechanism
Posted on: 12 January 2026
Preprint posted on 30 November 2025
Categories: cell biology
Context
Cells adhere to their environment through integrin adhesion complexes (IACs), with focal adhesions (FAs) localized at the cell periphery and reticular adhesions (RAs) as well as fibrillar adhesions (FBs) closer to the cell center. Dysregulation in signaling through IACs enables cancer metastasis and resistance to therapy. IACs are therefore crucial therapeutic targets.
The CMSC (Cortical Microtubule Stabilizing Complex) protein, KANK2, is a multifunctional scaffold protein that localizes to FAs and controls cell motility as well as crosstalk between actin and microtubules. The core rationale of the study highlighted here is to investigate the reason behind previously detected conflicting effects of KANK2 on melanoma cell migration: it reduced migration in a MDA-MB-435S cell line yet increased it in the RPMI-7951 cell line. The rationale of the study is also centered around how KANK2 decides which partner to interact with – talin1 or talin2.
Key findings of the preprint
Finding 1: KANK2 is a versatile scaffold
KANK2 is far more versatile than previously thought. KANK2 localizes to distinct integrin adhesion complexes (FA, FB and RA) in RPMI-7951 melanoma cells. Amazingly, KANK2 switched its interacting partner depending on its locations, that is FA or FB. At cell edge FA’s, KANK2 interacted with Talin1 to maintain cell size and shape. At cell centre FB’s, KANK2 interact with Talin2 and controlled adhesion sliding and motility.
Finding 2: KANK2 role in migration and drug sensitivity is cell type dependen
A major finding is that the role of KANK2 is highly dependent on the cell’s specific “adhesome” profile. In some melanoma cells (MDA-MB-435S), KANK2 is located in FAs and its knockdown reduces migration and increases sensitivity to chemotherapy (PTX). However, in RPMI-7951 cells, KANK2 is located in FAs and FBs and its knockdown mimics the disappearance of FBs, thus increases migration and has no effect on drug sensitivity. Therefore, this discrepancy is linked to the presence of FBs in RPMI-7951 cells, which act as a “brake” on migration when KANK2 is present.
Finding 3: Feedback Loop of extracellular matrix
In RPMI-7951 cells, removing αV integrins generates a compensatory feedback loop, and boosts the secretion of pro-metastatic proteins like Tenascin C and TGF-ß1. This observation indicate that cells try to maintain “homeostasis”, when primary players are lost. This may be one of the possible explanations for why integrin-targeted therapies have not been successful in patients.
What I like most about the preprint
I really liked the “surprise”: the unexpected outcome that the removal of the key adhesion protein, KANK2, augments migration, thus acting as molecular “brake” in certain melanoma cells. Further, I enjoyed the clear demonstration of KANK2 switching partners: interacting with Talin1 at the cell edge to regulate cell adhesion, and Talin2 at the cell center to regulate cell sliding. Importantly, this tells us that just the mere presence or absence of a protein is not always key to understanding the molecular mechanism. Spatial and temporal localization is key in understanding and subsequently the design of targeted therapies in disease models.
Significance of the study.
Despite assuring pre-clinical trials of integrin-targeted drugs, clinical trials have consistently failed; this remains a major hurdle, which is attributed to the complexity of integrin biology. Functional differences in cell-type context and the biochemical explanation provided in this study address some of the outstanding pharmacological challenges. Targeted therapy approaches should move beyond integrins and rather focus on “bridge” proteins (such as Talin and KANK) that could possibly be more effective.
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