In its active form, the GTP-binding protein rab8 interacts with a stress-activated protein kinase.

Ren, Mindong; Zeng, Jin; Lemos-Chiarandini, Carmen De; Rosenfeld, Melvin G.; Adesnik, Milton; Sabatini, David D.

doi:10.1073/pnas.93.10.5151

Cited by 92 publications

(68 citation statements)

References 48 publications

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“…GCK/MAP4K2 interacts with the GTPbound form of Rab8 preferentially over the GDP-bound form, and the interaction requires the intact effector region of Rab8. This suggests that GCK/MAP4K2 might act as an effector of Rab8 (14). Since our present study indicated that the CNH domain in MAP4K4 interacts with Rap2, it is interesting to hypothesize that some of the CNH domains in the STE20 group kinases may share a region that mediates interactions with small GTP-binding proteins.…”

Section: Discussionmentioning

confidence: 68%

“…The CNH domain is also present in the C-terminal portions of GCK-I and -IV subfamilies of the STE20 group kinases (5, 6). GCK/MAP4K2, which belongs to the GCK-I subfamily, interacts with Rab8 small GTP-binding protein through its C-terminal portion containing the CNH domain (14). GCK/MAP4K2 interacts with the GTPbound form of Rab8 preferentially over the GDP-bound form, and the interaction requires the intact effector region of Rab8.…”

Section: Discussionmentioning

confidence: 99%

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Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 as a Putative Effector of Rap2 to Activate the c-Jun N-terminal Kinase

Machida

Umikawa

Takei

et al. 2004

Journal of Biological Chemistry

119

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Little is known about the specific signaling roles of Rap2, a Ras family small GTP-binding protein. In a search for novel Rap2-interacting proteins by the yeast two-hybrid system, we isolated isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a previously described but uncharacterized isoform. Other isoforms of MAP4K4 in humans and mice are known as hematopoietic progenitor kinase (HPK)/ germinal center kinase (GCK)-like kinase and Nck-interacting kinase, respectively. MAP4K4 belongs to the STE20 group of protein kinases and regulates c-Jun Nterminal kinase (JNK). MAP4K4 interacted with Rap2 through its C-terminal citron homology domain but did not interact with Rap1 or Ras. Interaction with Rap2 required the intact effector region of Rap2. MAP4K4 interacted preferentially with GTP-bound Rap2 over GDP-bound Rap2 in vitro. In cultured cells, MAP4K4 colocalized with Rap2, while a mutant MAP4K4 lacking the citron homology domain failed to do so. Furthermore, Rap2 enhanced MAP4K4-induced activation of JNK. These results suggest that MAP4K4 is a putative effector of Rap2 mediating the activation of JNK by Rap2.Rap2 belongs to the Ras family of small GTP-binding proteins. The mammalian Ras family consists of Ras proteins (Ha-Ras, Ki-Ras, and N-Ras), Rap proteins (Rap1A, Rap1B, Rap2A, and Rap2B), R-Ras, R-Ras2/TC21, R-Ras3/M-Ras, Ral proteins (RalA and RalB), Rheb, Rin, and Rit (for a review, see Ref.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 as a Putative Effector of Rap2 to Activate the c-Jun N-terminal Kinase

Machida

Umikawa

Takei

et al. 2004

Journal of Biological Chemistry

119

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“…A likely explanation is that Rab8 regulates a pathway where a specific membrane traffic route participates in remodeling the cell shape in response to different signals. Rab8 is known to interact with the germinal center kinase, a protein involved in TNF-alpha signaling (Ren et al, 1996). There is also a connection of the Rab8-interacting protein optineurin (FIP-2) to TNF-alpha-mediated signals (Li et al, 1998;Schwamborn et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…This TNF-alpha inducible protein links Rab8 to huntingtin and modulates cell morphogenesis to some extent. Rab8-GTP also binds Rabip8/GCK, a participant in TNF-alpha-mediated processes (Ren et al, 1996), indicating a likely role for Rab8 in regulating membrane transport linked to stress responses and differentiation.…”

Section: Introductionmentioning

confidence: 99%

A Rab8-specific GDP/GTP Exchange Factor Is Involved in Actin Remodeling and Polarized Membrane Transport

Hattula

Furuhjelm

Arffman

et al. 2002

MBoC

185

218

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The mechanisms mediating polarized delivery of vesicles to cell surface domains are poorly understood in animal cells. We have previously shown that expression of Rab8 promotes the formation of new cell surface domains through reorganization of actin and microtubules. To unravel the function of Rab8, we used the yeast two-hybrid system to search for potential Rab8-specific activators. We identified a coil-coiled protein (Rabin8), homologous to the rat Rabin3 that stimulated nucleotide exchange on Rab8 but not on Rab3A and Rab5. Furthermore, we show that rat Rabin3 has exchange activity on Rab8 but not on Rab3A, supporting the view that rat Rabin3 is the rat equivalent of human Rabin8. Rabin8 localized to the cortical actin and expression of Rabin8 resulted in remodeling of actin and the formation of polarized cell surface domains. Activation of PKC by phorbol esters enhanced translocation of both Rabin8 and Rab8-specific vesicles to the outer edge of lamellipodial structures. Moreover, coexpression of Rabin8 with dominant negative Rab8 (T22N) redistributes Rabin8 from cortical actin to Rab8-specific vesicles and promotes their polarized transport to cell protrusions. The C-terminal region of Rabin8 plays an essential role in this transport. We propose that Rabin8 is a Rab8-specific activator that is connected to processes that mediate polarized membrane traffic to dynamic cell surface structures.

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“…Although hematopoietic progenitor protein kinase 1 is restricted to cells of hematopoietic lineage, both MLK3 and germinal center kinase are widely expressed in cell and tissue types (35,70). Interestingly it has been shown that hematopoietic progenitor protein kinase 1 can be recruited to lipid rafts (71), and germinal center kinase is found at Golgi and plasma membranes (72). One of the major functions ascribed to MLK3 is as a MAPKKK for activation of the JNK pathway.…”

Section: Discussionmentioning

confidence: 99%

Cdc42 Induces Activation Loop Phosphorylation and Membrane Targeting of Mixed Lineage Kinase 3

Du¹,

Böck²,

Schachter³

et al. 2005

Journal of Biological Chemistry

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Mixed lineage kinase 3 (MLK3) functions as a mitogen-activated protein kinase kinase kinase to activate multiple mitogen-activated protein kinase pathways. Our current studies demonstrate that lack of MLK3 blocks signaling of activated Cdc42 to c-Jun N-terminal kinase, giving strong support for the idea that Cdc42 is a physiological activator of MLK3. We show herein that Cdc42, in a prenylationdependent manner, targets MLK3 from a perinuclear region to membranes, including the plasma membrane. Cdc42-induced membrane targeting of MLK3 is independent of MLK3 catalytic activity but depends upon an intact Cdc42/Rac-interactive binding motif, consistent with MLK3 membrane translocation being mediated through direct binding of Cdc42. Phosphorylation of the activation loop of MLK3 requires MLK3 catalytic activity and is induced by Cdc42 in a prenylation-independent manner, arguing that Cdc42 binding is sufficient for activation loop autophosphorylation of MLK3. However, membrane targeting is necessary for full activation of MLK3 and maximal signaling to JNK. We previously reported that MLK3 is autoinhibited through an interaction between its N-terminal SH3 domain and a proline-containing sequence found between the leucine zipper and the CRIB motif of MLK3. Thus we propose a model in which GTP-bound Cdc42/Rac binds MLK3 and disrupts SH3-mediated autoinhibition leading to dimerization and activation loop autophosphorylation. Targeting of this partially active MLK3 to membranes likely results in additional phosphorylation events that fully activate MLK3 and its ability to maximally signal through the JNK pathway.

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In its active form, the GTP-binding protein rab8 interacts with a stress-activated protein kinase.

Cited by 92 publications

References 48 publications

Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 as a Putative Effector of Rap2 to Activate the c-Jun N-terminal Kinase

Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 as a Putative Effector of Rap2 to Activate the c-Jun N-terminal Kinase

A Rab8-specific GDP/GTP Exchange Factor Is Involved in Actin Remodeling and Polarized Membrane Transport

Cdc42 Induces Activation Loop Phosphorylation and Membrane Targeting of Mixed Lineage Kinase 3

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