Guanine nucleotide exchange factor Kalirin-7 (Kal-7) is a key factor in synaptic plasticity and plays an important regulatory role in the brain. Abnormal synaptic function leads to the weakening of cognitive functions such as learning and memory, accompanied by abnormal expression of Kal-7, which in turn induces a variety of neurodegenerative diseases. Exercise can upregulate the expression of Kal-7 in related brain regions to alleviate neurodegenerative diseases. By reviewing the literature on Kal-7 and neurodegenerative diseases, as well as the research progress of exercise intervention, this paper summarizes the role and possible mechanism of Kal-7 in the improvement of neurodegenerative diseases by exercise and provides a new rationale for the basic and clinical research on the prevention and treatment of neurodegenerative diseases by exercise.
Humans ; Neurodegenerative Diseases/therapy* ; Guanine Nucleotide Exchange Factors/metabolism* ; Exercise Therapy

OBJECTIVETo study the influence of lipopolysaccharide (LPS) on the permeability of rat brain microvascular endothelial cells (BMECs) and possible molecular mechanism.

METHODSMonolayers of primary rat BMECs were separated and cultured, and then treated with (LPS group) or without LPS (control group). The barrier integrity was measured by transendothelial electrical resistance (TEER) assay. The degrees of RhoA activation were determined by Pull-down assay. The expression levels of p115RhoGEF, zonula occludens-1 (ZO-1), occludin and claudin-5 proteins were detected by Western blot analysis.

RESULTSThe average TEER values of rat BMECs in the LPS group were 108.3±4.2 Ω•cm2 and 85.4±2.5 Ω•cm2 respectively 3 and 12 hrs after LPS treatment, which were significantly lower than that in the control group (159.0±8.6 Ω•cm2). Compared with the control group, the activity of RhoA started to increase 5 minutes after LPS treatment, and the expression of p115RhoGEF protein started to increase 1 hr after LPS treatment and the cellular protein levels of ZO-1, occludin and claudin-5 decreased significantly 3 hrs after LPS treatment in the LPS group (P<0.05).

CONCLUSIONSLPS may activate the p115RhoGEF/RhoA pathway and decrease protein expression of ZO-1, occludin and claudin-5, resulting in an increased permeability of rat BMECs.

Animals ; Brain ; blood supply ; Capillary Permeability ; drug effects ; Electric Impedance ; Endothelial Cells ; drug effects ; metabolism ; Guanine Nucleotide Exchange Factors ; analysis ; Lipopolysaccharides ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Rho Guanine Nucleotide Exchange Factors ; Tight Junctions ; chemistry ; rhoA GTP-Binding Protein ; analysis

The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.
Autism Spectrum Disorder/metabolism* ; Cell Movement/genetics* ; Humans ; Interneurons/metabolism* ; Neurodevelopmental Disorders/genetics* ; Neurons/metabolism* ; Rho Guanine Nucleotide Exchange Factors/genetics*

Adult ; Aged ; Aged, 80 and over ; Female ; Guanine Nucleotide Exchange Factors ; genetics ; metabolism ; Humans ; Keratin-18 ; genetics ; metabolism ; Lymph Nodes ; metabolism ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; RNA, Messenger ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; T-Lymphoma Invasion and Metastasis-inducing Protein 1

Previously, we demonstrated that the p190 Rho guanine nucleotide exchange factor (p190RhoGEF) was induced following CD40 stimulation of B cells. In this study, we examined whether p190RhoGEF and a downstream effector molecule RhoA are required for B cell differentiation. Expression of p190RhoGEF positively correlated with the expression of surface markers and transcriptional regulators that are characteristic of mature B cells with plasma cell (PC) phenotypes. Moreover, either the overexpression of p190RhoGEF or the expression of a constitutively active RhoA drove cellular differentiation toward PC phenotypes. B cell maturation was abrogated in cells that overexpressed p190RhoGEF and a dominant-negative form of RhoA simultaneously. CD40-mediated maturation events were also abrogated in cells that overexpressed either dominant-negative p190RhoGEF or RhoA. Together, these data provide evidence that p190RhoGEF signaling through RhoA in CD40-activated B cells drives the induction of the PC differentiation.
Animals ; B-Lymphocytes/*cytology/*metabolism ; Cell Differentiation/genetics/*physiology ; Cell Line ; Cells, Cultured ; Female ; Guanine Nucleotide Exchange Factors/genetics/*metabolism ; Humans ; Lymphocyte Activation/genetics/*physiology ; Mice ; Mice, Inbred BALB C ; Plasma Cells/*cytology/*metabolism ; rhoA GTP-Binding Protein/genetics/metabolism

p21-activated kinase (PAK)-interacting exchange factor (PIX) is known to be involved in regulation of Cdc42/Rac GTPases and PAK activity. PIX binds to the proline-rich region of PAK, and regulates biological events through activation of Cdc42/Rac GTPase. To further investigate the role of PIX we produced monoclonal antibodies (Mab) against beta PAK. Three clones; N-C6 against N-terminal half and C-A3 and C-B7 against C- terminal half of beta PAK were generated and characterized. N-C6 Mab detected beta PAK as a major band in most cell lines. C-A3 Mab recognizes GIT-binding domain (GBD), but it does not interfere with GIT binding to beta PAK. Using C-A3 Mab possible beta PAK interaction with actin in PC12 cells was examined. beta PAK Mab (C-A3) specifically precipitated actin of the PC12 cell lysates whereas actin Mab failed to immunoprecpitate beta PAK. Co-sedimentation of PC12 cell lysates with the polymerized F-actin resulted in the recovery of most of beta PAK in the cell lysates. These results suggest that beta PAK may not interact with soluble actin but with polymerized F-actin and revealed that beta PAK constitutes a functional complex with actin. These data indicate real usefulness of the beta PAK Mab in the study of beta PAK role(s) in regulation of actin cyoskeleton.
Actins/*metabolism ; Animals ; Antibodies, Monoclonal/immunology ; Cell Cycle Proteins/immunology/metabolism/*physiology ; Cell Line, Tumor ; Cytoskeletal Proteins/metabolism ; Epitope Mapping ; Guanine Nucleotide Exchange Factors/immunology/metabolism/*physiology ; Immunoprecipitation ; Mice ; Microfilaments/*physiology ; Protein Structure, Tertiary ; Rats ; Research Support, Non-U.S. Gov't

OBJECTIVETo investigate the relationship between the expression of T lymphoma invasion and metastasis inducing factor 1 (Tiam1) and the progression, metastasis, TNM stage, and histological types of lung carcinoma.

METHODSImmunohistochemistry was performed to detect the expression of Tiam1 in 116 lung carcinoma specimens. The expression intensity (measured in positive unit, PU) of Tiam1 in these tissues was assessed quantitatively using Imagepro Plus image analysis software.

RESULTSThe PU of Tiam1 was significantly greater in primary lung carcinomas with lymph node metastases than in those without metastases (t=-2.089, P=0.039). Lung cancers of TNM stage II-IV had stronger expression than those of stage I (t=-2.272, P=0.025). The PU of Tiam1 differed significantly between different histological types of lung cancer, and squamouscell cell carcinoma had a lower PU than adenocarcinoma, large cell carcinoma and small cell carcinoma (P<0.05). The intensity of Tiam1 expression was not associated with the patients' gender, age, general types, smoking history, pneumoconiosis or differentiation of lung carcinoma.

CONCLUSIONThese results strongly suggest that Tiam1 is an invasion and metastasis inducing factor of lung carcinoma. The overexpression of Tiam1 is closely associated with lymph node metastases, TNM stage and histological types of lung carcinoma.

Adenocarcinoma ; metabolism ; pathology ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Female ; Guanine Nucleotide Exchange Factors ; metabolism ; Humans ; Immunohistochemistry ; Lung Neoplasms ; metabolism ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; T-Lymphoma Invasion and Metastasis-inducing Protein 1

OBJECTIVETo explore biological aspects of Tiam1 gene expression in nasopharyngeal carcinoma cells.

METHODSTiam1/C1199HA expression plasmids were transfected into nasopharyngeal carcinoma cells of C666-1 and CNE1 by lipofectamine2000. RT-PCR, real-time PCR and Western blot Analyses were performed to evaluate the expression of Tiam1 mRNA and protein levels, respectively. In vitro cell adhesion, wound healing and matrigel invasion assays were used to study the biological impact of Tiam1 on cell adhesion, mobility and invasion.

RESULTSTiam1 over expression significantly increased the abilities of adhesion, migratory and invasion of C666-1 and CNE1 cells, comparing with that of the control untransfected cells (P < 0.05).

CONCLUSIONTiam1 expression correlates with the invasion and metastasis of nasopharyngeal carcinoma cells.

Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Gene Expression Regulation, Neoplastic ; Guanine Nucleotide Exchange Factors ; genetics ; metabolism ; physiology ; Humans ; Nasopharyngeal Neoplasms ; metabolism ; pathology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Plasmids ; RNA, Messenger ; metabolism ; T-Lymphoma Invasion and Metastasis-inducing Protein 1

OBJECTIVETo investigate the expression of T lymphoma invasion and metastasis inducing factor 1 (Tiam1) in breast carcinomas, and explore its association with the clinicopathological features of breast carcinoma.

METHODSImmunohistochemistry was used to detect Tiam1 expression in normal breast tissue and 126 breast carcinoma tissues, and the expression levels of Tiam1 mRNA and protein were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting, respectively.

RESULTSThe expression of Tiam1 was significantly higher in breast carcinomas than in normal breast tissue (P<0.05). Tiam1 expression was not correlated to the age of the patients or the histological type (P>0.05), but to lymph node metastasis and clinical stages of the tumor (P<0.01). Tiam1 mRNA and protein expressions were stronger in breast carcinoma cell line MDA-MB-435 with high metastatic potential than in breast carcinoma cell line MCF-7.

CONCLUSIONTiam1 is closely related to the metastasis of breast carcinoma, and may play an important role in promoting metastasis of breast carcinoma.

Adult ; Aged ; Breast Neoplasms ; metabolism ; pathology ; Cell Line, Tumor ; Female ; Guanine Nucleotide Exchange Factors ; genetics ; metabolism ; Humans ; Lymphatic Metastasis ; Middle Aged ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphoma Invasion and Metastasis-inducing Protein 1

OBJECTIVE: To investigate the effect of T lymphoma invasion and metastasis 1 (Tiam 1) overexpression in head and neck squamous cell carcinoma (HNSCC) cells. METHOD: Endogenous expression of Tiam 1 in 8 head and neck squamous cell carcinoma cell (HNSCC) lines was investigated by real-time RT-PCR. A lentivirus vector containing Tiaml was transfected into UM-SCC-47 cells, a head and neck squamous cell carcinoma cell line with little endogenous Tiaml expression. Stable clone, obtained by G418 screening, were assayed by RT-PCR and Western blot to validate the gene expression efficiency. The biological behaviors of the transduced cells were determined by cell counting, MTT and in-vitro migration assay. RESULT: Tiam 1 gene was highly expressed in M2 cell line and it's low level expression was found in UM-SCC-47. Cell counting and MTT assay showed that over-expression of Tiaml significantly promoted cell proliferation (P < 0.05). The cell monolayers overexpressed Tiaml that resulted in a significant increasment of cell migration in infected head and neck squamous cell carcinoma cell lines (P < 0.05). CONCLUSION Tiam 1 gene plays an important role in the growth and migration in head and neck squamous cell carcinoma cell lines. It may be a useful marker for metastasis of head and neck squamous cell carcinoma.
Blotting, Western ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Guanine Nucleotide Exchange Factors ; genetics ; metabolism ; Head and Neck Neoplasms ; metabolism ; pathology ; Humans ; Squamous Cell Carcinoma of Head and Neck ; T-Lymphoma Invasion and Metastasis-inducing Protein 1 ; Transfection