Ras GTPase-activating-like protein IQGAP1 (p195) [KIAA0051]
Cell senescence - an irreversible proliferation arrest - is one of the possible cellular responses to stress. There is a vast variety of stimuli, extrinsic and intrinsic, known to induce senescence, and several molecular pathways involved in the process; yet much still remains to be explained. Senescent cells can communicate with neighboring cells through secreted factors such as cytokines and chemokines. Several years ago it was shown that cells can also communicate in a more direct manner by an exchange of proteins via cellular bridges (CBs). Recent studies show that in senescent cells the intensity of such transfer increases. The research also revealed that Cdc42 and actin polymerization are indispensable for this process to occur. Here, we evaluate the hypothesis that, apart from actin and Cdc42, also IQGAP1 could be involved in direct intercellular communication. Our results showed that direct transfer occurred preferentially between senescent cells and that IQGAP1 was not essential for this process. Interestingly, cells harboring mutated IQGAP1 had altered morphology and were characterized by decreased proliferation, increased time of division and appearance of some senescence markers (increased activity of senescence-associated β-galactosidase and induction of senescence-associated secretory phenotype). Our findings suggest that IQGAP1 dysfunction can induce senescence.
- Cellular bridges (CBs)
- Intercellular communication
- Tunneling nanotubes (TNTs)
- Vascular smooth muscle cells (VSMCs)
Hyaluronan-binding protein 1 (HABP1), a multi-compartmental, multi-functional protein has a wide range of functions, which can be attributed to its ability to associate with a variety of cellular ligands. Earlier we have reported that HABP1 overexpression in rat normal fibroblasts (F-HABP07) shows chronic generation of reactive oxygen species (ROS), induction of autophagy, and apoptosis. However, a significant proportion of cells remained viable after the majority went through apoptosis from 60 to 72 h. In this study, an attempt has been made to delineate the cellular events in the declined population of surviving cells. It has been elucidated here that, these cells at later time points of growth, that is, 72 and 84 h, not only appeared to shrink but also are devoid of autophagic vacuoles and displayed polyploidy. F-HABP07 cells exhibited an altered cytoskeletal structure from their parental cell line F111, assumed to be caused upon inhibition of actin polymerization and decrease in IQ motif-containing GTPase activating protein 1 (IQGAP1), a key protein associated with maintenance of cytoskeletal integrity. Enhanced expression and nuclear localization of AKT observed in F-HABP07 cells appears to be contributing toward the maintenance of high ROS levels in these cells and also potentially modulating the IQGAP1 activity. These observations, in fact have been considered to result in sustained DNA damage, which then leads to increased expression of p53 and activation of p21 and carry out the cellular events responsible for senescence. Subsequent assessment of the presence of positive β-gal staining and enhanced expression of p16 in F-HABP07, confirmed that HABP1 overexpressing fibroblasts undergo senescence.
MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKCθ through phosphorylating PKCθ at Ser-538 residue, leading to activation of IKK/NF-κB. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORγt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting MAP4K3 (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.
- Autoimmune Diseases
- Protein-Serine-Threonine Kinases
- Autoimmune disease
- Cancer metastasis
- MAP4K3 (GLK)