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

Du, Yan; Böck, Barbara C.; Schachter, Karen; Chao, Mary; Gallo, Kathleen A.

doi:10.1074/jbc.m502671200

Cited by 63 publications

(63 citation statements)

References 70 publications

(36 reference statements)

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“…Thus, exposure to Tat and gp120 resulted in rapid autophosphorylation of MLK3 in neurons, at key regulatory sites within the kinase activation loop (31). This is consistent with Tator gp120-mediated activation of MLK3, given that autophosphorylation at Thr 277 and Ser 181 is an obligatory intermediate step of MLK3 activation, following its dimerization in response to specific stimuli such as Cdc42 (31,32).…”

Section: Tat Induces Phosphorylation Of Mlk3 In Neuronssupporting

confidence: 57%

Inhibition of Mixed Lineage Kinase 3 Prevents HIV-1 Tat-Mediated Neurotoxicity and Monocyte Activation

Sui

Fan

Sniderhan

et al. 2006

The Journal of Immunology

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The HIV-1 gene products Tat and gp120 are toxic to neurons and can activate cells of myeloid origin, properties that are thought to contribute to the clinical manifestations of HIV-1-associated dementia (HAD). To investigate the intracellular signaling mechanisms involved in these events, the effect of Tat and gp120 on mixed lineage kinase (MLK) 3 activation was examined. Tat and gp120 were shown to induce autophosphorylation of MLK3 in primary rat neurons; this was abolished by the addition of an inhibitor of MLK3 (CEP1347). CEP1347 also enhanced survival of both rat and human neurons and inhibited the activation of human monocytes after exposure to Tat and gp120. Furthermore, overexpression of wild-type MLK3 led to the induction of neuronal death, whereas expression of a dominant negative MLK3 mutant protected neurons from the toxic effects of Tat. MLK3-dependent downstream signaling events were implicated in the neuroprotective and monocyte-deactivating pathways triggered by CEP1347. Thus, the inhibition of p38 MAPK and JNK protected neurons from Tat-induced apoptosis, whereas the inhibition of p38 MAPK, but not of JNK, was sufficient to prevent Tat- and gp120-mediated activation of monocytes. These results suggest that the normal function of MLK3 is compromised by HIV-1 neurotoxins (Tat, gp120), resulting in the activation of downstream signaling events that result in neuronal death and monocyte activation (with release of inflammatory cytokines). In aggregate, our data define MLK3 as a promising therapeutic target for intervention in HAD.

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Section: Tat Induces Phosphorylation Of Mlk3 In Neuronssupporting

confidence: 57%

Inhibition of Mixed Lineage Kinase 3 Prevents HIV-1 Tat-Mediated Neurotoxicity and Monocyte Activation

Sui

Fan

Sniderhan

et al. 2006

The Journal of Immunology

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“…These proteins function as molecular switches between GDP-bound (inactive) and GTP-bound (active) states involved in the regulation of actin cytoskeleton (Rudolph et al 1999). CDC42 induces autophosphorylation of the activation loop and membrane targeting of mixed lineage kinase 3, a kinase that is autoinhibited by its SH3 domain, and a proline-rich region located between its leucine zipper and CRIB domains (Du et al 2005). RhoU, an atypical member of the CDC42 family, contains proline-rich N-terminal and C-terminal extensions.…”

Section: Class Imentioning

confidence: 99%

SH3 domains: modules of protein–protein interactions

2012

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Src homology 3 (SH3) domains are involved in the regulation of important cellular pathways, such as cell proliferation, migration and cytoskeletal modifications. Recognition of polyproline and a number of noncanonical sequences by SH3 domains has been extensively studied by crystallography, nuclear magnetic resonance and other methods. High-affinity peptides that bind SH3 domains are used in drug development as candidates for anticancer treatment. This review summarizes the latest achievements in deciphering structural determinants of SH3 function.

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“…We previously discovered that MLK3 is autoinhibited through its src-homology-3 domain (Zhang and Gallo, 2001). Activated Cdc42/Rac increases MLK3 catalytic activity (Teramoto et al, 1996) through binding to the Cdc42/Rac-interactive binding motif (Bock et al, 2000) and promoting activation loop (auto)phosphorylation (Du et al, 2005). On the basis of work from our laboratory and by others (Leung and Lassam, 1998;Vacratsis and Gallo, 2000;Nihalani et al, 2001), we propose that binding of the small GTPase, Cdc42 or Rac, disrupts src-homology-3-mediated autoinhibition, promoting leucine zipper-mediated dimerization and subsequent transphosphorylation within the catalytic domain to yield active MLK3.…”

Section: Introductionmentioning

confidence: 99%

MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells

2010

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The malignant phenotype in breast cancer is driven by aberrant signal transduction pathways. Mixed-lineage kinase-3 (MLK3) is a mammalian mitogen-activated protein kinase kinase kinase (MAP3K) that activates multiple MAPK pathways. Depending on the cellular context, MLK3 has been implicated in apoptosis, proliferation, migration and differentiation. Here we investigated the effect of MLK3 and its signaling to MAPKs in the acquisition of malignancy in breast cancer. We show that MLK3 is highly expressed in breast cancer cells. We provide evidence that MLK3's catalytic activity and signaling to c-jun N-terminal kinase (JNK) is required for migration of highly invasive breast cancer cells and for MLK3-induced migration of mammary epithelial cells. Expression of active MLK3 is sufficient to induce the invasion of mammary epithelial cells, which requires AP-1 activity and is accompanied by the expression of several proteins corresponding to AP-1-regulated invasion genes. To assess MLK3's contribution to the breast cancer malignant phenotype in a more physiological setting, we implemented a strategy to inducibly express active MLK3 in the preformed acini of MCF10A cells grown in 3D Matrigel. Induction of MLK3 expression dramatically increases acinar size and modestly perturbs apicobasal polarity. Remarkably, MLK3 expression induces luminal repopulation and suppresses the expression of the pro-apoptotic protein BimEL, as has been observed in Her2/Neu-expressing acini. Taken together, our data show that MLK3-JNK-AP-1 signaling is critical for breast cancer cell migration and invasion. Our current study uncovers both a proliferative and novel antiapoptotic role for MLK3 in the acquisition of a malignant phenotype in mammary epithelial cells. Thus, MLK3 may be an important therapeutic target for the treatment of invasive breast cancer.

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

Cited by 63 publications

References 70 publications

Inhibition of Mixed Lineage Kinase 3 Prevents HIV-1 Tat-Mediated Neurotoxicity and Monocyte Activation

Inhibition of Mixed Lineage Kinase 3 Prevents HIV-1 Tat-Mediated Neurotoxicity and Monocyte Activation

SH3 domains: modules of protein–protein interactions

MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells

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