The University of Tokyo · Neuroscience
Professor Yoshitaka Fukada's research lab focuses on the molecular mechanisms underlying circadian rhythms in vertebrates, with a particular emphasis on the post-translational regulation of core clock proteins such as CRY1/2 and BMAL1. The lab investigates how phosphorylation by kinases like DYRK1A and GSK-3β controls the stability and activity of these proteins, thereby shaping circadian oscillations in both central and peripheral clocks. Additionally, the lab explores the roles of signaling molecules such as MAPK and G protein γ-subunits in modulating clock function and phototransduction pathways. Their work integrates biochemistry, cell biology, and molecular physiology to uncover fundamental principles of biological timekeeping.
Figures are computed from collected data and may differ slightly.
Cryptochrome 1 and 2 act as essential components of the central and peripheral circadian clocks for generation of circadian rhythms in mammals. Here we show that mouse cryptochrome 2 (mCRY2) is phosphorylated at Ser-557 in the liver, a well characterized peripheral clock tissue. The Ser-557-phosphorylated form accumulates in the liver during the night in parallel with mCRY2 protein, and the phosphorylated form reaches its maximal level at late night, preceding the peak-time of the protein abunda
In vertebrates, mitogen-activated protein kinase (MAPK) exhibits circadian activation in several clock structures and likely participates in the timekeeping mechanism of the circadian clock. Here we show that MAPK associates with a basic helix-loop-helix-PAS transcription factor BMAL1, a positive regulator for the autoregulatory feedback loop of the circadian oscillator. MAPK phosphorylates BMAL1 at multiple sites, including Ser-527, Thr-534, and Ser-599, in vitro, and BMAL1:CLOCK-induced transa
Circadian molecular oscillation is generated by a transcription/translation-based feedback loop in which CRY proteins play critical roles as potent inhibitors for E-box-dependent clock gene expression. Although CRY2 undergoes rhythmic phosphorylation in its C-terminal tail, structurally distinct from the CRY1 tail, little is understood about how protein kinase(s) controls the CRY2-specific phosphorylation and contributes to the molecular clockwork. Here we found that Ser557 in the C-terminal tai
G protein gamma-subunits are isoprenylated and carboxyl-methylated at the C-terminal cysteine, which is indispensable for the function of photoreceptor G protein transducin (T alpha beta gamma). However, the physiological role of the methylation and its reversibility have been unclear. Here we isolated methylated and non-methylated forms of farnesylated T beta gamma, and demonstrated that the methylation remarkably facilitates not only the membrane association of T beta gamma but also the subuni
Melanopsin is a vertebrate non-visual opsin and functions as a circadian photoreceptor in mammalian retinas. Here we found the expression of two kinds of melanopsin genes in the chicken pineal gland and identified the presence of five isoforms derived from these two genes. Reconstitution of the recombinant proteins with 11-cis-retinal revealed that at least two of these melanopsin protein isoforms can function as blue-sensitive photopigments with absorption maxima at 476-484nm. These values are
The functional characterization of the chicken pineal clock molecules supports the key roles of BMAL1, BMAL2 and CLOCK which contribute to the E-box-dependent transcriptional regulation in the circadian clock system.
The photochemical reaction of cyclopentatrienylidene 11-cis-locked-rhodopsin derived from cyclopentatrienylidene 11-cis-locked-retinal and cattle opsin was spectrophotometrically studied. The difference absorption spectrum between the cyclopentatrienylidene 11-cis-locked-rhodopsin and its retinal oxime had its maximum at 495 nm (P-495). Irradiation of P-495 at -196 degrees C with either blue light or orange light caused no spectral change, supporting the cis-trans isomerization hypothesis for fo
Suprachiasmatic nucleus circadian oscillatory protein (SCOP) is a member of the leucine-rich repeat (LRR)-containing protein family. In addition to circadian expression in the rat hypothalamic suprachiasmatic nucleus, SCOP is constitutively expressed in neurons throughout the rat brain. Here we found that a substantial amount of SCOP was localized in the brain membrane rafts, in which only K-Ras was abundant among Ras isoforms. SCOP interacted directly through its LRR domain with a subset of K-R
We detected rhodopsin gene expression in the pigeon lateral septum, a photosensitive deep brain region that is responsible for the photoperiodic gonadal response. The nucleotide sequence of the deep brain rhodopsin cDNA clone exactly matched that of the retinal one, indicating that a single rhodopsin gene is transcribed in the two tissues. Immunohistochemical analysis localized rhodopsin in the cerebrospinal fluid-contacting neurons, which have been assumed to be photoreceptive cells in the deep
Casein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned whether the degradation of the core circadian machinery is a critical step in clock regulation. Prior cell-based studies found that CK1 phosphorylation of PER2 at Ser478 recruits the ubiquitin E3 ligase β-TrCP, leading to PER2 degradation. Creation
In many vertebrates, the pineal gland serves as a photoreceptive neuroendocrine organ. Morphological and functional similarities between the pineal and retinal photoreceptor cells indicate their close evolutionary relationship, and hence the comparative studies on the pineal gland and the retina are the keys to deciphering the evolutionary traces of the vertebrate photoreceptive organs. Several studies have suggested common genetic and molecular mechanisms responsible for their similarities, but
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