Kindlins

Source: PIB

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Context:

• A new study has investigated the influence of Kindlins-- adapter proteins that exist inside cells of vertebrates, in various cancers.
• Since this protein is central to many signaling pathways, targeting it could lead to new cancer treatments that address multiple aspects of the disease at once.

Details:

About Kindlins:

Kindlins are a family of proteins that play a crucial role in various cellular processes, particularly in integrin signaling. Integrins are cell surface receptors that facilitate cell-extracellular matrix (ECM) adhesion, which is fundamental for many cellular functions, including migration, proliferation, and survival. The proper functioning of integrins is essential for various physiological processes such as wound healing, immune responses, and embryonic development.

Background on Kindlins:

• Adapter proteins located inside vertebrate cells, attached to cell membranes.
• Involved in transferring extracellular mechanical cues to biochemical signals.
• Play a critical role in signaling pathways affecting various cellular functions.

 Structure and Function

• Kindlins belong to the FERM (4.1 protein, ezrin, radixin, moesin) domain-containing family of proteins.
• There are three members of the Kindlin family in mammals: Kindlin-1, Kindlin-2, and Kindlin-3.

Each of these proteins is encoded by different genes:

1. Kindlin-1 (FERMT1): Primarily expressed in epithelial cells.
2. Kindlin-2 (FERMT2): Ubiquitously expressed in all tissues.
3. Kindlin-3 (FERMT3): Expressed in hematopoietic cells.

• Kindlins enhance the affinity of integrins for their ECM ligands through direct binding, thus playing a pivotal role in integrin activation. This binding is critical for the inside-out signaling pathway that regulates integrin activation and adhesion strength.

 Significance of the Study

Contribution to Cancer Biology:

• Offers insights into the interplay between tumors and their microenvironment.
• Establishes a foundation for future research on Kindlins in cancer treatment.

Importance of Kindlins in Cancer

Mutations and Homeostasis:

• Kindlins can undergo mutations due to exposure to carcinogens (g., nicotine, UV rays).
• Disruption in Kindlins affects mechano-chemical signaling, leading to loss of homeostasis and potential cancer development.

Significance of Research:

• Understanding genetic alterations in Kindlins is key to uncovering mechanisms of cancer growth.
• The study conducted at N. Bose National Centre for Basic Sciences involved data from 10,000 patients across 33 cancer types.

Key Findings of the Study

Roles of Specific Kindlin Proteins:

• Kindlin 1: Regulates immune microenvironment in breast cancer.
• Kindlin 2: Governs cancer-specific metabolic regulation (TCA cycle and glycolysis) and HIPPO signaling, influencing cell migration and invasion.

Tumor Progression and Metastasis:

• Kindlins are implicated in processes such as tumor progression, metastasis, and epithelial-mesenchymal transition (EMT).
• EMT allows cancer cells to become more mobile, aiding in the spread of cancer.

Role in Disease:

Dysfunction or mutations in Kindlin proteins can lead to various diseases:

• Kindler Syndrome: Caused by mutations in the Kindlin-1 gene, leading to skin fragility, blistering, and photosensitivity.
• LAD-III (Leukocyte Adhesion Deficiency Type III): Associated with mutations in Kindlin-3, resulting in defective leukocyte adhesion and severe recurrent infections.
• Cancer: Aberrant expression of Kindlin-2 has been implicated in cancer progression and metastasis. Elevated levels of Kindlin-2 are often associated with poor prognosis in several cancers.

Methodology

Use of Structural and Functional Genomics:

• Employed genomic tools to analyze the influence of Kindlin family proteins on mechano-chemical signaling.
• Established associations with clinical parameters, highlighting Kindlins' role across various cancer stages and subtypes.

Implications for Cancer Treatment

Potential Therapeutic Targets:

• Kindlins represent promising targets for mechano-modulatory cancer therapeutics.
• A comprehensive understanding of Kindlin interactions may lead to innovative treatment strategies.

Challenges in Oncology:

• Addressing chemoresistance and tumor relapse through targeted therapies focusing on Kindlins.

Conclusion

• Kindlins are integral to the normal functioning of integrin-mediated cell-ECM interactions and have significant implications for health and disease. Ongoing research into Kindlin proteins continues to reveal their fundamental roles and therapeutic potential, making them an exciting area of study in cellular biology and medicine.

Source:

https://pib.gov.in/PressReleaseIframePage.aspx?PRID=2039090

https://pubmed.ncbi.nlm.nih.gov/26729028/

https://www.cell.com/current-biology/pdf/S0960-9822(10)01588-5.pdf

PRACTICE QUESTION With reference to Kindlins, consider the following statements: Kindlins are a family of proteins that play a critical role in integrin activation and function. Mutations in the genes encoding Kindlins can lead to severe congenital diseases. Kindlins are primarily found in the extracellular matrix of connective tissues. Which of the statements given above is/are correct? (a) 1 and 2 only (b) 2 and 3 only (c) 1 and 3 only (d) 1, 2, and 3 Answer: a