Talins, hopes and promises

Talins were the fi rstly identifi ed cytoplasmic protein partners of integrins. Vertebrates have two talin genes, TLN1 and TLN2, which encode Talin-1 and Talin-2, respectively. Talin-1 is essential for cell adhesion and motility and is the primary talin component of focal adhesions. Many studies have demonstrated, involvement of talins in different mechanisms inside many body cells, induction of some diseases. Moreover, recent and ongoing research indicates the diagnostic and prognostic roles of talins in various clinical settings especially in critically ill patients. Additionally, talins may be a good target for treatment of certain types of diseases. Talins levels are altered in various physiological and pathological conditions indicating its importance and possible use as a biomarker or a tool for diagnosis or treatment. However, further research using talins in various clinical settings will prove its cost-effectiveness and clinical usefulness. Review Article Talins, hopes and promises Mohamed S. Attia Gaballah*, Mahmoud Youns, Zeinab A. Hassan Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt Dates: Received: 03 July, 2017; Accepted: 05 August, 2017; Published: 07 August, 2017 *Corresponding author: Mohamed S. Attia Gaballah, Msc, Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt, E-mail:


Talins and platelet aggregation
It has been shown that integrins are important for hemostasis and thrombosis because they trigger both platelet adhesion and aggregation. They are heterodimeric transmembrane receptors composed of an -and a subunit that are expressed in a low affi nity state in resting platelets. After activation, mediated by other platelet receptors, integrins shift to a high affi nity state and effi ciently bind their ligands [1].
The role of talin in mammalian integrin function in vivo was examined by selectively disrupting the talin1 gene in mouse platelet precursor megakaryocytes. Talin null megakaryocytes produced circulating platelets that displayed normal morphology while manifested profoundly impaired hemostatic function. Specifi cally, platelet-specifi c deletion of talin1 led to spontaneous hemorrhage and pathological bleeding. These experiments demonstrated that talin is required for inside-out activation of platelet integrins in hemostasis and thrombosis [2,3].

Talins and B-lymphocytes homing in lymph nodes
CD19 cre-mediated depletion of talin1 in B cells shows that talin1 was not required for B-cell generation in the bone marrow or for the entry of immature B cells to the white pulp of the spleen. Furthermore, loss of talin1 also did not affect B-cell maturation into follicular B cells but compromised differentiation of marginal zone B cells. Nevertheless, serum IgM and IgG levels remained normal.
However, ex-vivo analysis of talin1-defi cient spleen B cells indicated an important role for talin1 in lymphocyte functionassociated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) activation stimulated by canonical agonists, but not in B-cell chemotaxis. As a result, talin1 null B splenocytes could not enter lymph nodes nor return to the bone marrow. Talin1 defi ciency in B cells was also impaired in the humoral response to a T cell-dependent antigen.
Collectively, these results indicate that talin1 is not required for follicular B-cell maturation in the spleen or homeostatic humoral immunity but is critical for integrin-dependent B lymphocyte emigration to lymph nodes and optimal immunity against T-dependent antigens [4].

Talins and T cell activation and T cell stopping
It has been revealed that T cell-antigen presenting cell (APC) contact initiates T cell activation and is maintained by the integrin lymphocyte function-associated antigen-1 (LFA-1).

Talin1-defi cient T cells showed defects in contact-dependent
T cell stopping and proliferation. While, did not form stable interactions with APCs, transient contacts were suffi cient to induce signaling.
In contrast to prior models, LFA-1 was polarized to T cell:APC contacts in talin1-defi cient T cells but vinculin and F-actin polarization at the immune synapse was impaired.
These results Indicate that T cell proliferation requires sustained, talin1-mediated T cell:APC interactions and that talin1 is necessary for F-actin polarization and the stability of immune synapses [5]. Moreover,Talin1-defi cient precursors normally express osteoclast differentiation markers when exposed to M-CSF and receptor activator of nuclear factor B (RANK) ligand, but attach to substrate and migrate poorly, stopping their development into mature resorptive cells. In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an 5 fold increase in bone mass. Osteoclast-specifi c deletion of Rap1 (CtsK-Rap1), which promotes talin/ integrin recognition, yields similar osteopetrotic mice.

Talins and NK cells cytotoxicity
The fact that the osteopetrosis of CtsK-TLN1 and CtsK-Rap1 mice is substantially more severe than that of those missing v3 is likely due to added failed activation of 1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending infl ammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function and their selective inhibition, in mature osteoclasts, retards pathological bone loss [8]. This data suggests a critical role for talin in Treg cell-mediated maintenance of immune homeostasis [9].

Talin is a mechanosensitive molecule in health and disease
It has recently proved that Talin is one of a handful molecules that can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind and recruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great importance in the fi eld of mechanobiology due to its plasticity in undergoing conformational changes under force stimulation beside its cellular localization that bridges the cytoskeleton with the extra cellular matrix. In addition to these roles in healthy cells, the dysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransduction precipitate changes in cell spreading, migration, and survival.
Novel data have implicated a role for talin in diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talin structure, its relationship to binding partners, and its role in disease states [10]. Furthermore, increased concentrations of Ca2 + -binding proteins calgranulins A and B in psoriatic plasma were also observed, confi rming previous reports, and appeared to be relevant to the increase of cytoskeletal components. Decreased fi brinogen fragments were another notable change in psoriatic plasma [11].

Talins and rheumatoid arthritis
It has been reported that, plasma talin is a clinically useful new biomarker for diagnosis and monitoring for rheumatoid arthritis using the commercially available enzyme linked immunosorbent assay (ELISA) kits [12].

Talins and Multiple Sclerosis
Previously, it has been identifi ed anti-Talin-1 antibodies in the serum of MS. Recently, they measured the serum soluble Talin-1 (sTalin-1) levels by enzyme-linked immunosorbent assay. The serum sTalin-1 levels were signifi cantly higher in patients with MS than in normal controls and in the acute phase of disease than in the remission phase. Interestingly, serum sTalin-1 levels were associated with a sustained increase in disability after MS attack but not with serum anti-Talin-1 antibody levels. sTalin-1 may be a biomarker for the acute phase of MS and may be used for the short-term prognosis of MS [13].

Conclusion
For a critical care clinician, Talin analysis could be particularly helpful as a diagnostic or prognostic tool in many types of diseases. The presence of elevated levels of talin in various critically ill clinical states and its correlation with disease severity augments its role as a prognostic biomarker in clinical practice and as a good target for treatment of diseases.
However, further studies using this biomarker in various clinical settings will ultimately prove their cost-effectiveness and clinical usefulness.