scholarly journals c-Src-Mediated Epithelial Cell Migration and Invasion Regulated by PDZ Binding Site

2007 ◽  
Vol 28 (2) ◽  
pp. 642-655 ◽  
Author(s):  
Martin Baumgartner ◽  
Gerald Radziwill ◽  
Mihaela Lorger ◽  
Andreas Weiss ◽  
Karin Moelling
Keyword(s):  
Cell Migration ◽  
Basement Membrane ◽  
Normal Growth ◽  
Growth Conditions ◽  
Regulatory Function ◽  
Migration And Invasion ◽  
Src Tyrosine Kinase ◽  
Surrounding Matrix ◽  
Cell Matrix ◽  
C Terminus

ABSTRACT c-Src tyrosine kinase controls proliferation, cell adhesion, and cell migration and is highly regulated. A novel regulatory mechanism to control c-Src function that has recently been identified involves the C-terminal amino acid sequence Gly-Glu-Asn-Leu (GENL) of c-Src as ligand for PDZ domains. Herein, we determined the biological relevance of this c-Src regulation in human breast epithelial cells. The intact GENL sequence maintained c-Src in an inactive state in starved cells and restricted c-Src functions that might lead to metastatic transformation under normal growth conditions. c-Src with a C-terminal Leu/Ala mutation in GENL (Src-A) promoted the activation and translocation of cortactin and focal adhesion kinase and increased the motility and persistence of cell migration on the basement membrane. Src-A promoted increased extracellular proteolytic activity, and in acinar cultures, it led to the escape of cells through the basement membrane into the surrounding matrix. We ascribe the regulatory function of C-terminal Leu to the role of GENL in modulating c-Src activity downstream of cell matrix adhesion. We propose that the C terminus of c-Src via its GENL sequence presents a mechanism that restricts c-Src in epithelia and prevents progression toward an invasive phenotype.

The positive regulatory function of the 5'-proximal open reading frames in GCN4 mRNA can be mimicked by heterologous, short coding sequences

1988 ◽  
Vol 8 (9) ◽  
pp. 3827-3836
Author(s):  
N P Williams ◽  
P P Mueller ◽  
A G Hinnebusch
Keyword(s):  
Translational Control ◽  
Normal Growth ◽  
Regulatory Elements ◽  
Growth Conditions ◽  
Open Reading Frames ◽  
Regulatory Function ◽  
Yeast Saccharomyces Cerevisiae ◽  
Reading Frame ◽  
Yeast Genes ◽  
Reading Frames

Translational control of GCN4 expression in the yeast Saccharomyces cerevisiae is mediated by multiple AUG codons present in the leader of GCN4 mRNA, each of which initiates a short open reading frame of only two or three codons. Upstream AUG codons 3 and 4 are required to repress GCN4 expression in normal growth conditions; AUG codons 1 and 2 are needed to overcome this repression in amino acid starvation conditions. We show that the regulatory function of AUG codons 1 and 2 can be qualitatively mimicked by the AUG codons of two heterologous upstream open reading frames (URFs) containing the initiation regions of the yeast genes PGK and TRP1. These AUG codons inhibit GCN4 expression when present singly in the mRNA leader; however, they stimulate GCN4 expression in derepressing conditions when inserted upstream from AUG codons 3 and 4. This finding supports the idea that AUG codons 1 and 2 function in the control mechanism as translation initiation sites and further suggests that suppression of the inhibitory effects of AUG codons 3 and 4 is a general consequence of the translation of URF 1 and 2 sequences upstream. Several observations suggest that AUG codons 3 and 4 are efficient initiation sites; however, these sequences do not act as positive regulatory elements when placed upstream from URF 1. This result suggests that efficient translation is only one of the important properties of the 5' proximal URFs in GCN4 mRNA. We propose that a second property is the ability to permit reinitiation following termination of translation and that URF 1 is optimized for this regulatory function.

Molecular analysis of GCN3, a translational activator of GCN4: evidence for posttranslational control of GCN3 regulatory function

1988 ◽  
Vol 8 (11) ◽  
pp. 4808-4820
Author(s):  
E M Hannig ◽  
A G Hinnebusch
Keyword(s):  
Amino Acid ◽  
Normal Growth ◽  
Growth Conditions ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Noncoding Dna ◽  
Physical Description ◽  
Amino Acid Availability ◽  
Translational Activator ◽  
Starvation Conditions

GCN4 encodes a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. The GCN3 product is a positive regulator required for increased synthesis of GCN4 protein in amino acid-starved cells. GCN3 appears to act indirectly by antagonizing GCD-encoded negative regulators of GCN4 expression under starvation conditions; however, GCN3 can also suppress the effects of gcd12 mutations under nonstarvation conditions. These results imply that the GCN3 product can promote either repression or activation of GCN4 expression depending on amino acid availability. We present a complete physical description of the GCN3 gene and its transcript, plus measurements of GCN3 expression at the transcriptional and translational levels under different growth conditions. GCN3 encodes a 305-amino-acid polypeptide with no significant homology to any other known protein sequence. GCN3 mRNA contains no leader AUG codons, and no potential GCN4 binding sites were found in GCN3 5' noncoding DNA. In accord with the absence of these regulatory sequences found at other genes in the general control system, GCN3 mRNA and a GCN3-lacZ fusion enzyme are present at similar levels under both starvation and nonstarvation conditions. These data suggest that modulation of GCN3 regulatory function in response to amino acid availability occurs posttranslationally. A gcn3 deletion leads to unconditional lethality in a gcd1-101 mutant, supporting the idea that GCN3 is expressed under normal growth conditions and cooperates with the GCD1 product under these circumstances to carry out an essential cellular function. We describe a point mutation that adds three amino acids to the carboxyl terminus of GCN3, which inactivates its positive regulatory function required under starvation conditions without impairing its ability to promote functions carried out by GCD12 under nonstarvation conditions.

scholarly journals Molecular analysis of GCN3, a translational activator of GCN4: evidence for posttranslational control of GCN3 regulatory function.

1988 ◽  
Vol 8 (11) ◽  
pp. 4808-4820 ◽  
Author(s):  
E M Hannig ◽  
A G Hinnebusch
Keyword(s):  
Amino Acid ◽  
Normal Growth ◽  
Growth Conditions ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Noncoding Dna ◽  
Physical Description ◽  
Amino Acid Availability ◽  
Translational Activator ◽  
Starvation Conditions

GCN4 encodes a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. The GCN3 product is a positive regulator required for increased synthesis of GCN4 protein in amino acid-starved cells. GCN3 appears to act indirectly by antagonizing GCD-encoded negative regulators of GCN4 expression under starvation conditions; however, GCN3 can also suppress the effects of gcd12 mutations under nonstarvation conditions. These results imply that the GCN3 product can promote either repression or activation of GCN4 expression depending on amino acid availability. We present a complete physical description of the GCN3 gene and its transcript, plus measurements of GCN3 expression at the transcriptional and translational levels under different growth conditions. GCN3 encodes a 305-amino-acid polypeptide with no significant homology to any other known protein sequence. GCN3 mRNA contains no leader AUG codons, and no potential GCN4 binding sites were found in GCN3 5' noncoding DNA. In accord with the absence of these regulatory sequences found at other genes in the general control system, GCN3 mRNA and a GCN3-lacZ fusion enzyme are present at similar levels under both starvation and nonstarvation conditions. These data suggest that modulation of GCN3 regulatory function in response to amino acid availability occurs posttranslationally. A gcn3 deletion leads to unconditional lethality in a gcd1-101 mutant, supporting the idea that GCN3 is expressed under normal growth conditions and cooperates with the GCD1 product under these circumstances to carry out an essential cellular function. We describe a point mutation that adds three amino acids to the carboxyl terminus of GCN3, which inactivates its positive regulatory function required under starvation conditions without impairing its ability to promote functions carried out by GCD12 under nonstarvation conditions.

scholarly journals The C-Terminus Tail Regulates ERK3 Kinase Activity and Its Ability in Promoting Cancer Cell Migration and Invasion

2020 ◽  
Vol 21 (11) ◽  
pp. 4044 ◽  
Author(s):  
Lobna Elkhadragy ◽  
Hadel Alsaran ◽  
Weiwen Long
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Cell Migration And Invasion ◽  
C Terminus

Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family. It harbors a kinase domain in the N-terminus and a long C-terminus extension. The C-terminus extension comprises a conserved in ERK3 and ERK4 (C34) region and a unique C-terminus tail, which was shown to be required for the interaction of ERK3 with the cytoskeletal protein septin 7. Recent studies have elucidated the role of ERK3 signaling in promoting the motility and invasiveness of cancer cells. However, little is known about the intramolecular regulation of the enzymatic activity and cellular functions of ERK3. In this study, we investigated the role of the elongated C-terminus extension in regulating ERK3 kinase activity and its ability to promote cancer cell migration and invasion. Our study revealed that the deletion of the C-terminus tail greatly diminishes the ability of ERK3 to promote the migration and invasion of lung cancer cells. We identified two molecular mechanisms underlying this effect. Firstly, the deletion of the C-terminus tail decreases the kinase activity of ERK3 towards substrates, including the oncogenic protein steroid receptor co-activator 3 (SRC-3), an important downstream target for ERK3 signaling in cancer. Secondly, in line with the previous finding that the C-terminus tail mediates the interaction of ERK3 with septin 7, we found that the depletion of septin 7 abolished the ability of ERK3 to promote migration, indicating that septin 7 acts as a downstream effector for ERK3-induced cancer cell migration. Taken together, the findings of this study advance our understanding of the molecular regulation of ERK3 signaling by unraveling the role of the C-terminus tail in regulating ERK3 kinase activity and functions in cancer cells. These findings provide useful insights for the development of therapeutic agents targeting ERK3 signaling in cancer.

The urokinase plasminogen activator and its receptor

2005 ◽  
Vol 93 (02) ◽  
pp. 205-211 ◽  
Author(s):  
Daniela Alfano ◽  
Paola Franco ◽  
Immacolata Vocca ◽  
Nadia Gambi ◽  
Viviana Pisa ◽  
...  
Keyword(s):  
Cell Migration ◽  
Plasminogen Activator ◽  
Cancer Metastasis ◽  
Dynamic Control ◽  
Migration And Invasion ◽  
Cell Matrix ◽  
Pathological Conditions ◽  
Type Plasminogen Activator ◽  
Apoptosis Ratio ◽  
Extracellular Proteolysis

SummaryThe urinary-type plasminogen activator, or uPA, controls matrix degradation through the conversion of plasminogen into plasmin and is regarded as the critical trigger for plasmin generation during cell migration and invasion, under physiological and pathological conditions (such as cancer metastasis).The proteolytic activity of uPA is responsible for the activation or release of several growth factors and modulates the cell survival/apoptosis ratio through the dynamic control of cell-matrix contacts. The urokinase receptor (uPAR), binding to the EGF-like domain of uPA, directs membrane-associated extracellular proteolysis and signals through transmembrane proteins, thus regulating cell migration, adhesion and cytoskeletal status. However, recent evidence highlights an intricate relationship linking the uPA/uPAR system to cell growth and apoptosis.

scholarly journals Integrin α9 Suppresses Hepatocellular Carcinoma Metastasis by Rho GTPase Signaling

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-Li Zhang ◽  
Xin Xing ◽  
Li-Bo Cai ◽  
Lei Zhu ◽  
Xiao-Mei Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Migration ◽  
Focal Adhesion ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Migration And Invasion ◽  
Integrin Subunit ◽  
Src Tyrosine Kinase ◽  
Tumor Cell Migration

Integrin subunit alpha 9 (ITGA9) mediates cell-cell and cell-matrix adhesion, cell migration, and invasion through binding different kinds of extracellular matrix (ECM) components. However, its potential role and underlying molecular mechanisms remain unclear in hepatocellular carcinoma (HCC). Here, we found that ITGA9 expression was obviously decreased in patients with HCC, which was negatively correlated with HCC growth and metastasis. ITGA9 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Our data demonstrated that the inhibitory effect of ITGA9 on HCC cell motility was associated with reduced phosphorylation of focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src), disrupted focal adhesion reorganization, and decreased Rac1 and RhoA activity. Our data suggest ITGA9, as a suppressor of HCC, prevents tumor cell migration and invasiveness through FAK/Src-Rac1/RhoA signaling.

scholarly journals Intracellular nanovesicles mediate integrin trafficking during cell migration

2020 ◽  
Author(s):  
Gabrielle Larocque ◽  
Penelope J. La-Borde ◽  
Beverley J. Wilson ◽  
Nicholas I. Clarke ◽  
Daniel J. Moore ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Surface ◽  
Membrane Trafficking ◽  
Surface Proteins ◽  
Migration And Invasion ◽  
Rab Gtpase ◽  
Surface Receptors ◽  
C Terminus ◽  
Transport Vesicle ◽  
Important Regulator

Membrane traffic is an important regulator of cell migration through the endocytosis and recycling of cell surface receptors such as integrin heterodimers. Intracellular nanovesicles (INVs), are a recently identified class of transport vesicle that are involved in multiple membrane trafficking steps including the recycling pathway. The only known marker for INVs is Tumor Protein D54 (TPD54/TPD52L2), a member of the TPD52-like protein family. Overexpression of TPD52-like family proteins in cancer has been linked to poor prognosis and an aggressive metastatic phenotype which suggests cell migration may be altered under these conditions. Here we show that TPD54 associates with INVs by directly binding high curvature membrane via a conserved positively charged motif in its C-terminus. We describe how other members of the TPD52-like family are also associated with INVs and we document the Rab GTPase complement of all INVs. Depletion of TPD52-like proteins inhibits cell migration and invasion; and we show that this is likely due to altered integrin recycling. Our study highlights the involvement of INVs in the trafficking of cell surface proteins to generate biologically important outputs in health and disease.

scholarly journals The positive regulatory function of the 5'-proximal open reading frames in GCN4 mRNA can be mimicked by heterologous, short coding sequences.

1988 ◽  
Vol 8 (9) ◽  
pp. 3827-3836 ◽  
Author(s):  
N P Williams ◽  
P P Mueller ◽  
A G Hinnebusch
Keyword(s):  
Translational Control ◽  
Normal Growth ◽  
Regulatory Elements ◽  
Growth Conditions ◽  
Open Reading Frames ◽  
Regulatory Function ◽  
Yeast Saccharomyces Cerevisiae ◽  
Reading Frame ◽  
Yeast Genes ◽  
Reading Frames

Translational control of GCN4 expression in the yeast Saccharomyces cerevisiae is mediated by multiple AUG codons present in the leader of GCN4 mRNA, each of which initiates a short open reading frame of only two or three codons. Upstream AUG codons 3 and 4 are required to repress GCN4 expression in normal growth conditions; AUG codons 1 and 2 are needed to overcome this repression in amino acid starvation conditions. We show that the regulatory function of AUG codons 1 and 2 can be qualitatively mimicked by the AUG codons of two heterologous upstream open reading frames (URFs) containing the initiation regions of the yeast genes PGK and TRP1. These AUG codons inhibit GCN4 expression when present singly in the mRNA leader; however, they stimulate GCN4 expression in derepressing conditions when inserted upstream from AUG codons 3 and 4. This finding supports the idea that AUG codons 1 and 2 function in the control mechanism as translation initiation sites and further suggests that suppression of the inhibitory effects of AUG codons 3 and 4 is a general consequence of the translation of URF 1 and 2 sequences upstream. Several observations suggest that AUG codons 3 and 4 are efficient initiation sites; however, these sequences do not act as positive regulatory elements when placed upstream from URF 1. This result suggests that efficient translation is only one of the important properties of the 5' proximal URFs in GCN4 mRNA. We propose that a second property is the ability to permit reinitiation following termination of translation and that URF 1 is optimized for this regulatory function.

scholarly journals Intracellular nanovesicles mediate α5β1 integrin trafficking during cell migration

2021 ◽  
Vol 220 (10) ◽  
Author(s):  
Gabrielle Larocque ◽  
Daniel J. Moore ◽  
Méghane Sittewelle ◽  
Cansu Kuey ◽  
Joseph H.R. Hetmanski ◽  
...  
Keyword(s):  
Cell Migration ◽  
Membrane Trafficking ◽  
Migration And Invasion ◽  
Rab Gtpase ◽  
Surface Receptors ◽  
C Terminus ◽  
Transport Vesicles ◽  
Important Regulator ◽  
Recycling Pathway ◽  
Α5β1 Integrin

Membrane traffic is an important regulator of cell migration through the endocytosis and recycling of cell surface receptors such as integrin heterodimers. Intracellular nanovesicles (INVs) are transport vesicles that are involved in multiple membrane trafficking steps, including the recycling pathway. The only known marker for INVs is tumor protein D54 (TPD54/TPD52L2), a member of the TPD52-like protein family. Overexpression of TPD52-like family proteins in cancer has been linked to poor prognosis and an aggressive metastatic phenotype, which suggests cell migration may be altered under these conditions. Here, we show that TPD54 directly binds membrane and associates with INVs via a conserved positively charged motif in its C terminus. We describe how other TPD52-like proteins are also associated with INVs, and we document the Rab GTPase complement of all INVs. Depletion of TPD52-like proteins inhibits cell migration and invasion, while their overexpression boosts motility. We show that inhibition of migration is likely due to altered recycling of α5β1 integrins in INVs.

scholarly journals MOLECULAR DETERMINANTS OF THE ENDOCYTIC PROTEIN EPSIN CONTROLLING ITS LOCALIZATION AND FUNCTION IN CANCER CELL MIGRATION AND INVASION

2020 ◽  
Author(s):  
Kayalvizhi Madhivanan ◽  
Lingyan Cao ◽  
Chris J. Staiger ◽  
R. Claudio Aguilar
Keyword(s):  
Cell Migration ◽  
Mammalian Cells ◽  
Protein Localization ◽  
Adaptor Proteins ◽  
Lipid Binding ◽  
Migration And Invasion ◽  
Binding Motifs ◽  
Enth Domain ◽  
C Terminus ◽  
And Function

ABSTRACTEpsins are endocytic adaptor proteins with signaling and endocytic functions. The three mammalian epsin paralogs are made of an Epsin N-Terminal Homology (ENTH) domain and an unstructured C-terminal region. The highly conserved ENTH domain plays a role in signaling by blocking RhoGAP activity and is required for cell migration in mammalian cells. However, our lab has previously shown that only epsin full length overexpression can enhance cell migration, but the ENTH domain alone cannot. Among the three Epsin paralogs, epsin 3 followed by epsin 2 were able to substantially enhance cell migration. This study is the first one to systematically and comprehensibly address the contribution of different motifs within the epsin C-terminus to enhance protein localization and cell migration. We show that is not the lipid-binding ENTH domain, but the C-terminus of epsin the one playing a major role in epsin association with sites of endocytosis. Further, we dissected the contribution of individual C-terminal endocytic (clathrin-, AP2-, Ubiquitin- and EH domain-binding) motifs for epsin localization. We found that while all motifs show a degree of synergism, the clathrin-binding motifs are the most important for epsin localization. Our study also showed that, these motifs (particularly the clathrin binding site) play an important role in sustaining endocytic site dynamics and cell migration.

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