Yue, Jianbo

岳劍波

Assistant Professor

e-mail: jyue@hkucc.hku.hk

Tel.: 2819-9162

• cADPR-mediated calcium signaling.

Mobilization of intracellular Ca²⁺ stores is involved in many diverse cell functions, including fertilization, muscle contraction, secretion of neurotransmitters, hormones and enzymes, and lymphocyte activation and proliferation.  Cyclic adenosine diphosphoribose (cADPR) is an endogenous Ca²⁺ mobilizing nucleotide present in many cell types and different species, including protozoa, plants, and animals.  cADPR is formed by ADP-ribosyl cyclases from nicotinamide adenine dinucleotide (NAD).  The main ADP-ribosyl cyclase is CD38, a multi-functional enzyme and a type II membrane protein.  It has been shown that many extracellular stimuli can induce cADPR production  that leads to calcium release or influx, establishing cADPR as a second messenger (Figure 1).  However, the molecular mechanisms mediating the stimulus-induced cADPR production have not been resolved.  In addition, although evidence indicates that the ryanodine receptor is the main intracellular target for cADPR, it is unclear whether cADPR elicits Ca²⁺ release by direct binding to the ryanodine receptor or via an accessory protein(s).  Given the pivotal role of cADPR-mediated calcium signaling pathway in a wide variety of cellular processes, it is of great interest to further dissect the molecular mechanism of the cADPR signaling pathway.

There are two specific aims in this research:

1. To define the signaling pathway mediating the stimulus-induced cADPR production in cells.

2. To identify protein components which are important for the calcium releasing activity of cADPR.

• Mitotic activation of Plk1 and Mos.

Mitosis is one of the most intricately orchestrated and spectacular events in cell biology.  The progression of M-phase is regulated by a cascade of protein phosphorylation and proteolysis events.  Errors in these processes can lead to chromosomal instability or aneuloidy, which is a hallmark of many diseases, including cancer.  The ERK1/ERK2 MAP kinases (MAPKs) and polo-like kinase 1(Plk1) are two mitotic kinases, and are transiently activated during mitosis.  The activations of both MAPK and Plk1 have been implicated in the spindle assembly checkpoint and in establishing the timing of an unperturbed mitosis.

Recently, I have identified the Mos proto-oncoprotein, a MAP kinase kinase kinase present at low levels in mitotic egg extracts, early embryos, and somatic cells, as the long-sought-after mitotic activator of p42 MAPK in Xenopus egg extracts.  Moreover, the activity of Mos was found to depend upon Cdc2-cyclin B-dependent phosphorylations and dephosphorylation, a previously unrecognized level of Mos regulation. I am currently identifying the downstream targets of the Mos/MEK/MAPK cascade required for spindle assemble checkpoint in somatic cells.

In addition, I have applied the tandem tag affinity purification approach to identify Plx1 interacting proteins in interphase and M-phase egg extracts.  Many Plx1 interacting proteins have been identified by this strategy, including proteins involved in Plk1’s established functions, such as G2 DNA damage checkpoint, centrosome maturation, chromosome alignment, APC/C activation, and cytokinesis, some of them have already been reported as Plk1 substrates or regulators.  I am currently characterizing some of these Plk-1 interacting proteins.

Overall, my long-term objective is to dissect the mechanism, function, and signal network of mitotic kinases (Figure 2).

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