GTK, a Src-related Tyrosine Kinase, Induces Nerve Growth Factor-independent Neurite Outgrowth in PC12 Cells through Activation of the Rap1 Pathway

Annerén, Cecilia; Reedquist, Kris A.; Bos, Johannes L.; Welsh, Michael

doi:10.1074/jbc.m003926200

Cited by 32 publications

(28 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it is notable that the rat homologue of Rak, called GTK, induces neurite outgrowth in rat pheochromocytoma PC12 cells through activation of a pathway that includes the adapter protein Shb and FAK. 20 As seen in BT474 cells, MCF-7 cells expressing Rak mutants did not incorporate BrdU (Fig. 7, Rak), while unfused GFP control incorporated BrdU readily (Fig.…”

Section: Rak Arrests Growth In Mcf-7 Breast Cancer Cellsmentioning

confidence: 99%

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

Meyer

Chang

et al. 2003

Intl Journal of Cancer

View full text Add to dashboard Cite

Rak is a 54 kDa protein tyrosine kinase originally isolated from breast cancer cells and expressed in epithelial cells. It resembles the protooncogene Src structurally but lacks an amino-terminal myristylation site and localizes to the nuclear and perinuclear regions of the cell. We report here that expression of Rak in 2 different breast cancer cell lines inhibits growth and causes G 1 arrest of the cell cycle. This growth inhibition is kinase-dependent but does not require the Rak SH2 or SH3 domain. Rak also binds to the pRb tumor-suppressor protein but inhibits growth even in cells that lack pRb. These results suggest that Rak regulates cell growth by phosphorylating perinuclear proteins and has a function that is distinct from the Src-related kinase family. Protein tyrosine kinases play key roles in signal transduction and influence a number of cellular processes that maintain the balance between proliferation, differentiation, senescence and apoptosis. Receptor tyrosine kinases such as HER2/neu and the EGFR are expressed in breast cancer and represent important therapeutic targets. In a screen for other protein kinases expressed in human breast cancer cell lines and tissues, 1 we identified the Rak tyrosine kinase, 2 simultaneously identified as FRK. 3 Rak is a member of a subfamily of Src-related tyrosine kinases that includes Sik, 4 Brk, 5 Gtk 6 and Bsk/Iyk. 7 The distinguishing features of this subfamily of kinases is that they are all expressed primarily in epithelial tissues and share greater identity within the group than to Src itself. The Rak-related kinases are distinct from CSK 8,9 subfamily because they contain a tyrosine near their carboxy termini.All Rak-related kinases contain SH2 and SH3 domains 10 at the amino termini and a kinase domain at the carboxy termini. SH2 domains bind to phosphorylated tyrosine residues, 11 whereas SH3 domains associate with proline-rich sequences of target proteins. 12 These domains are involved in both intermolecular associations that regulate signaling cascades and intramolecular associations that autoregulate protein kinase activity. [13][14][15] At its carboxy terminus, Rak has a kinase domain and associated autophosphorylation activity. 2 In addition, the carboxy-terminal tyrosine of Rak is phosphorylated in vitro by CSK, suggesting that this may be a regulatory site. 2 While Rak resembles Src structurally, it lacks the myristylation signal that localizes Src to the cell membrane. Instead, Rak contains a putative bipartite nuclear localization signal within its SH2 domain. Rak cofractionates with nuclear proteins in some cell lines 2 but is primarily perinuclear in others and was detected in the perinuclear region in the present study. Additionally, Rak associates with pRb during the G 1 and S phases of the cell cycle by interacting with the A/B pocket of pRb, and endogenous Rak is elevated during the G 1 phase of the cell cycle. 16 Nuclear localization has also been reported for the related murine Iyk. 17 Rak also contrasts with Src tyrosine kinase in its bi...

show abstract

Section: Rak Arrests Growth In Mcf-7 Breast Cancer Cellsmentioning

confidence: 99%

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

Meyer

Chang

et al. 2003

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…For example, Akt (Markus et al, 2002), cAMP (Weeks et al, 1991) and nitric oxide (Cogen and Cohen-Cory, 2000) modulate axon branching, which is differentially affected by trophic factors (Gallo and Letourneau, 1998;Szebenyi et al, 2001) and extracellular matrix molecules (Weeks et al, 1991). We propose that Rit activates a novel pathway to promote neurite outgrowth and branching (Kuo et al, 1996;Morooka and Nishida, 1998;Lehmann et al, 1999;Anneren et al, 2000;Brown et al, 2000;Ghil et al, 2000;Klocker et al, 2000;Burry, 2001). Candidate members of such a pathway may include novel protein kinases and/or additional members of the Ras superfamily of small GTPases.…”

Section: Rit and Extracellular Matrix Interactionsmentioning

confidence: 99%

Rit promotes MEK-independent neurite branching in human neuroblastoma cells

Hynds

Spencer

Andres

et al. 2003

Journal of Cell Science

View full text Add to dashboard Cite

Rit, by sequence homology, is a member of the Ras subfamily of small guanine triphosphatases (GTPases). In PC6 cells, Rit signals through pathways both common to and different from those activated by Ras to promote cell survival and neurite outgrowth. However, the specific morphological changes induced by Rit in human cells are not known. Here, we show in a human neuronal model that Rit increases neurite outgrowth and branching through MEK-dependent and MEK-independent signaling mechanisms, respectively. Adenoviral expression of wild-type or constitutively active Rit increased neurite initiation,elongation and branching on endogenous matrix or a purified laminin-1 substratum of SH-SY5Y cells as assessed using image analysis. This outgrowth was morphologically distinct from that promoted by constitutively active Ras or Raf (evidenced by increased branching and elongation). Constitutively active Rit increased phosphorylation of ERK 1/2, but not Akt, and the MEK inhibitor PD 098059 blocked constitutively active Rit-induced neurite initiation but not elongation or branching. These results suggest that Rit plays a key role in human neuronal development and regeneration through activating both known and as yet undefined signaling pathways.

show abstract

“…Certain of these genes, Ninjurin, Synaptotagmin, Synaptogyrin, and Rap1b, have already been partially characterized in vitro and/or in vivo, and have been implicated in axonal outgrowth, synaptic plasticity, and regeneration (20,(22)(23)(24)(25)(26)33). Synaptotagmin and Synaptogyrin are active throughout the entire synapse formation process, being involved in vesicle docking, exocytosis, and endocytosis of synaptic vesicles-and contribute to neurite extension (22,33).…”

Section: Coronin 1b and Rab13 Protein Expression Is Induced After Scmentioning

confidence: 99%

“…Rap1b is a small GTPase belonging to Ras superfamily of proteins, whose members may be involved in growth cone elongation, are induced by NGF, and can promote neurite outgrowth (34). Rap1 itself plays a role in the activation of the NGF-dependent ERK pathway, leading to axonal elongation in PC-12 cells (26). The cell adhesion molecule Ninjurin has also been reported to be induced by peripheral nerve injury, and promotes axonal and neurite outgrowth in sciatic nerve and DRG neurons following injury (20,35).…”

Section: Coronin 1b and Rab13 Protein Expression Is Induced After Scmentioning

confidence: 99%

See 1 more Smart Citation

In Vivo and in Vitro Characterization of Novel Neuronal Plasticity Factors Identified following Spinal Cord Injury

Giovanni

Biase

Yakovlev

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Following spinal cord injury, there are numerous changes in gene expression that appear to contribute to either neurodegeneration or reparative processes. We utilized high density oligonucleotide microarrays to examine temporal gene profile changes after spinal cord injury in rats with the goal of identifying novel factors involved in neural plasticity. By comparing mRNA changes that were coordinately regulated over time with genes previously implicated in nerve regeneration or plasticity, we found a gene cluster whose members are involved in cell adhesion processes, synaptic plasticity, and/or cytoskeleton remodeling. This group, which included the small GTPase Rab13 and actin-binding protein Coronin 1b, showed significantly increased mRNA expression from 7-28 days after trauma. Overexpression in vitro using PC-12, neuroblastoma, and DRG neurons demonstrated that these genes enhance neurite outgrowth. Moreover, RNAi gene silencing for Coronin 1b or Rab13 in NGF-treated PC-12 cells markedly reduced neurite outgrowth. Coronin 1b and Rab13 proteins were expressed in cultured DRG neurons at the cortical cytoskeleton, and at growth cones along with the pro-plasticity/regeneration protein GAP-43. Finally, Coronin 1b and Rab13 were induced in the injured spinal cord, where they were also co-expressed with GAP-43 in neurons and axons. Modulation of these proteins may provide novel targets for facilitating restorative processes after spinal cord injury.Traumatic injury to the spinal cord induces delayed biochemical responses that affect both cell loss and subsequent repair. Modulation of reparative processes includes factors involved in either facilitating or inhibiting neurite outgrowth, which are often regulated at the gene and protein levels after injury. Collectively, these factors likely determine in part the degree of anatomical and functional recovery after injury.Regeneration-associated proteins (RAGs) appear to play a role in plasticity and regeneration following SCI. 1 These include transcription factors (c-Jun), cytoskeletal components (T␣1), microtubule-associated proteins, growth-associated proteins (GAP-43, CAP-23), cell adhesion molecules (N-CAM, L1, TAG1), neurotrophic factors, cytokines, and extracellular matrix components (SNAP25, munc13, and cpg15/neuritin) (1-10). In some cases, these factors share common molecular pathways. GAP-43 and CAP-23 bind downstream to the cofactor PI(4,5)P(2), at plasmalemmal rafts, contributing to the regulation of actin and modulating neurite outgrowth in neuronallike cell lines (11,12). In other instances, a common downstream effector, such as neurotrophin-dependent intracellular cAMP, may serve to facilitate axonal regeneration by overcoming inhibition from factors such as myelin-associated glycoprotein (MAG) (13)(14)(15).Microarray technology provides a powerful tool for identifying molecular pathways involved in either endogenous neurotoxicity or regeneration/plasticity after SCI (16 -19). It allows concurrent analysis of thousands of genes and the identification of c...

show abstract

GTK, a Src-related Tyrosine Kinase, Induces Nerve Growth Factor-independent Neurite Outgrowth in PC12 Cells through Activation of the Rap1 Pathway

Cited by 32 publications

References 48 publications

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

Rit promotes MEK-independent neurite branching in human neuroblastoma cells

In Vivo and in Vitro Characterization of Novel Neuronal Plasticity Factors Identified following Spinal Cord Injury

Contact Info

Product

Resources

About