Cell, Developmental and Molecular Biology
what are the main components of the notch receptor
-1 extracellular component: notch extracellular domain which binds to the ligand -NICD -a transmembrane component which attaches the extracellular and intracellular domain
signal transduction molecules
-Transduce growth signal from cell surface to nucleus Within the nucleus, the expression and activity of transcription factors is regulated by signal transduction pathways.
Delta-Notch signaling is important for:
-conserved signaling pathway for development and homeostasis
What are the Notch ligands?
-jagged protein family: JAG1, JAG2 -Delta-like protein family -DLL1,DLL3, DLL4
downstream targets in Delta notch tumour cases
-promote cell proliferation -inhibit cell apoptosis -maintain cancer stem-like phenotypes examples: -lymphocytic leukaemias -non-small cell carcinomas -hepatocellular carcinoma
Hallmarks of cancer include
-sustaining proliferative signaling -evading growth factors -enabling replicative immortality -resisting angiogenesis - inducing angiogenesis -activating invasion and metastasis
What do DAG and IP3 do?
1. active protein kinase C (PKC) 2. Increase cytoplasmic calcium levels
What is a teratoma?
A tumor that arises from all 3 germinal layers (ectoderm, mesoderm, endoderm) • Rare germ cell tumours that most often develop in the ovary or testicle • <2% of all cancers in children and adolescents (<20 years old) • Can be malignant (immature) or benign (mature) • Contain mixed cell populations from all three germ layers e.g teeth, hair, nerves and muscle • Usually treated by surgery +/- follow up chemotherapy
How does Wee1 delay mitosis
By supressing the activity of the cyclin B1/cdc2 complex.
CDKs in the cell cycle
CDKs trigger the transition from G1 to S phase and from G2 to M phase by phosphorylating distinct sets of substrates. D type cyclins and CDK4 or CDK6 regulate events in the early G1 phase. Cyclin E-CDK2 triggers S phase, cyclin A-CDK2 and cyclin A-CDK1 regulate the completion of S phase. CDK1 cyclin B is responsible for mitosis
Cdc13
Cdc13 is a B-type cyclin required for Cdc activation and its localisation to the nucleus. It contains a sequence called the destruction box at the N-terminus, which is the target for the ubiquitin-dependent proteolytic degradation system. Destruction boxes are also characteristically found in other cyclins: cyclin A N-terminus, cyclins C, D and E C-terminus.
cdc2
Cdc2 (aka Cdk1), complexed with Cdc13, plays a central role in controlling the initiation of mitosis. Its activity at G2/M is mainly regulated by inhibitory phosphorylation and dephosphorylation on tyrosine 15 (Wee 1 or Mik 1 kinase and Cdc25 phosphatase). In addition to chromosome condensation, nuclear envelope breakdown is also catalysed by cdc2 (phosphorylation of nuclear envelope proteoglycans and laminin inhibits their ability to polymerise which causes the membrane to breakdown and remain that way until phosphatases can act on the laminins after telophase).
Cdc25A
Cdc25A (one of three human homologues of the fission yeast cdc25) is an 80-kDa phosphatase that exhibits cyclic accumulation in M. Cdc25B appears at S and peaks at G2. Cdc25C is predominately expressed in G2 and activated indirectly by cyclin B-cdc2 in a positive feedback loop.
the mitotic cell cycle
Cells increase in number by dividing; they do this through an ordered series of events, which involves: 1. Making more cellular contents (protein lipid, mitochondria etc) 1. Copying their genetic material 2. Segregating their cellular contents, including their DNA
what happens in telophase
Chromosomes decondense, nuclear envelope reforms, spindle disappears
What are cyclins
Cyclins are unstable proteins that are degraded via the ubiquitin / proteosome pathway. Phosphorylation-dependent ubiquitination, and subsequent degradation, depends upon the sequential action of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a protein-ubiquitin ligase (E3), e.g. members of the SCF family).
D and E cyclins
D- and E- cyclins are expressed during G0/G1 and are referred to as start cyclins. Start is also known as the restriction point in mammalian cells and is the point in late G1 in which the cell commits itself to another round of DNA replication.
describe the process of miosis
During meiosis, there will be two nuclear divisions, and the result will be four haploid nuclei. - daughter cell has only one of each kind of chromosome (23). - No replication of DNA occurs between meiosis I and meiosis II. The process of meiosis ensures that the next generation will have: 1. the diploid number of chromosomes (23, egg + 23, sperm) 2. a combination of traits that differs from that of either parent.
example of kinase regulation
Example: the PDGFR is capable of recruiting PI-3 kinase, PLCg, c-raf, p120rasGAP and src proteins. In contrast, CSF-1 receptor (c-fms) does not interact with PLCg.
whats G0?
G0 is a resting phase, the cell is out of cycle, e.g if it has been deprived of growth factors. Differentiated cells are normally in G0
is cyclin E induced later in the G1 phase than D type cyclins
In general, cyclin E is induced later in G1 than the D-type cyclins. E binds to cdk2 and is first synthesised during mid G1, its expression peaks at the G1/S transition or early S and then degrades as the cell progresses through S phase. The cyclin E-cdk2 complex has histone H1 kinase activity and is thought to be required for the initiation and progression of DNA replication (see also cdc2 later).
does p21 exist in an active or inactive state
In normal human diploid fibroblasts, p21 exists in quaternary complexes that contain cyclin, cdk and PCNA. In such complexes p21 can exist in either an active of inactive state dependent upon its stoichiometry (particularly when multiple p21 molecules as opposed to a single molecule is bound to the complex).
activated notch-delta signaling in tumour cells
Interaction between notch ligands( Jagged and Delta) and notch receptors, which trigger 2 consecutive proteolytic cleavages by the ADAM10 metalloprotease and γ-secretase complex which generate the ICN activating complex. This complex enters the nucleus and displaces corepressors (SMRT and CtBP1) that recruits MAML1 and p300. this signaling can be used to promote the progression of different cancer types.
the two phases of the mitotic cell cycle
Interphase Mitosis
What is gastrulation?
Invagination of blastocyst to form gastrula. Formation of three cell layer. an embryo transforms from an one-dimensional layer of epithelial cells, a blastula, and recognizes into a multilayered and multidimensional structure called the gastrula.
what is GLI-1
It is a glioblastoma-1 activator that encodes transcription factors which all contain conserved tandem c2-h2 zinc finger domains and a consensus histidine/ cysteine linker sequence between zinc fingers
Expression of a specific D-type cyclin (D1, D2 and D3)
It is tissue specific. eg. T lymphocytes express more D3 than D2 and are D1 negative. The absence of specific D cyclins in certain cell types may signal a switch between proliferation and differentiation. Unlike cdk4 that can be identified in fibroblasts and macrophages, cdk6 is most prominently expressed in lymphocytes. In the context of mitogen stimulation, cyclin D genes have been shown to be transcriptionally induced by, amongst others, c-Myc, AP-1, and NFkb.In respect to AP1 the C-jun and JunB ratios determine whether transcription is activated or repressedi.e. c-Jun induces expression whereas JunB represses cyclin D1 transcription
what does LOF mutations do in active wnt pathway
Loss of function mutations e.g ZNRF3 Activate B-Catenin independent WNT signaling cascades (e.g WNT/PCP)
class one homeobox (HOX) genes
Master regulatory genes • embryo pattern formation • organogenesis • cell differentiation • haematopoiesis HOX genes are turned on by a cascade of regulatory genes and they regulate the morphology of specific vertrebral and long bone elements
Hh Signaling and Cancer
Models of Hh signaling pathway activation in cancer. (A) Hh ligand-independent activation due to the mutations of Hh components, including mutations in PTCH, SMO, SUFU, and GLI amplifications. (B) Hh ligand-dependent autocrine activation due to excessive Hh ligands secreted by tumor cells to induce Hh signaling in tumor cells themselves. (C) Hh ligand-dependent paracrine activation due to excessive Hh ligands secreted by tumor cells to induce Hh signaling in nonneoplastic cells, such as fibroblasts and macrophages, which in turn secrete soluble mediators, such as IL-6, TNF-α, and VEGF to promote tumor growth. (D) Hh ligand-dependent reverse paracrine activation due to Hh ligands produced by stroma cells to induce Hh signaling in tumor cells.
embryonic stem cell cycle
Mouse embryo between - d4.5-d6 doubling time of ~10hr - d6.5 doubling time of ~4.4hr Mouse ES cells - Doubling time of ~11hr - Greatly reduced time in G phases - Increased time in S phase - Express high levels of cdk2 and cyclin A/E* - Hyperphosphorylation of Rb - Low in cyclin D - Consequence: Do not sense signals that impose - G1 checkpoint - Slow cell cycle - Modulate cyclins during cell cycle - Lack of G1 à Risk of mutations in ICM being transmitted to whole organism (and germline) à variant cells funneled directly to apoptosis pathway (*hES have high levels of CyclinD/cdk4)
What does NICD do once its cleaved from the transmembrane portion of the notch receptor
NICD gets free within the cytosol and binds to CSL and Mam which binds to p300. CSL, NICD, Mam and p300 translocate into the nucleus, where p300 acts as a histone acetylase. Afterwards notch targets the Myc, p21 and CD3 genes
p14
Not a CDKI but its coding sequences partially overlap with p16ink4a (ARF takes its name from this Alternative Reading Frame).
prophase II
Nuclear envelope disassembles Nucleolus disappears Spindle appears
What is homeosis?
Over 120 years ago William Bateson, proposed the term: "homeosis" to define "a change from something into the likeness of something else"
describe active Shh signaling
PTCH receptor protein receives the hedgehog protein and imparts the signal. Hh mediates the degradation of PTCH so SMO will not be degraded. The SMO protein gets into the plasma membrane through vesicle fusion and its first acted upon by kinases like PK1 and CK1. These kinases phosphorylate the c-terminal domain of SMO protein, as well as the cos-2 and FU proteins. The phosphorylated smo protein recruits cos-2 and FU proteins which leads to disassociation of cos-2/ Ci complex. From there the Ci protein gets off from the SUFU inhibitory protein and moves towards the nucleus. The non cleaved Ci protein gets to the nucleus and combined with CBP protein, they target the same hedgehog signaling genes. This acts as a transcription activator, which leads to the activation of hedgehog signaling genes in the cell. When this pathway is activated it upregulates PTCH, cycD1, Myc, Bcl-2, Nanog, SOX2 and leads to proliferation, angiogenesis, suppression of apoptosis and stem cell self-renewal.
which gene is responsible for eyeless drosophila
Pax6
PIP2 stands for
Phosphatidylinositol 4,5-bisphosphate
which amino acid stands for S/T
Phosphorylated serine or threonine
anaphase II
Sister chromatids separate become daughter chromosomes that move into the daughter nuclei.
what happens iin anaphase
Sister chromatids separate and move towards the spindle poles
telophase II
Spindle disappears Nuclear envelopes reform
what is the first step in the activation of cyclin-Cdk complexes
The first step in the activation of cyclin-Cdk complexes is the association of the cyclin subunit with a Cdk partner (this may require an as yet unidentified assembly factor - the chaperonin complex Cdc37-Hsp90 specifically interacts with Cdk4 and 6 and facilitate their assembly with cyclin D1 complexes in vitro, the Cip/Kip family may also play a role).
Describe interphase
The part of the cell cycle during which cells duplicate their chromosomes. Interphase has 3 periods; G1, S, and G2. 1. G1 (Gap 1) - a gap or pause after a proliferative stimulus, where little seems to happen, although there is a lot of biochemical activity. During this phase a commitment is made to enter S phase, based upon the following criteria: Has the cell grown enough to enter the cycle? Is the DNA intact? 2. S ("synthesis") phase - during this phase chromosomes are duplicated 3. G2 (Gap 2) - During this phase the cell prepares to enter mitosis and asks: Has DNA synthesis been completed properly?
Describe the delta-notch function normally
The signal receiving cell has an extracellular domain (NECD) and an intracellular domain (NICD). These domains are interconnected by transmembrane domain. The signal sending cell has an inactive delta ligand which needs to be activated (question 22). This delta ligand interacts with the extracellular domain of the signal receiving cell. Once DLL of sending cell binds to notch receptor of the receiving cell, ADAM protease which cleaves the extracellular domain of the notch receptor dislodges that component of the receiving cell. This is the S2 cleavage. S1 cleavage has happened during the processing of notch receptor. S2 cleavage is followed by s3 cleavage, where γ-secretase complex cleaves NICD from the transmembrane domain and after this it is released into the cell. NICD is translocated into the nucleus
somatic cells in the cell cycle
The somatic cell cycle depends on growth factors that activate the G1 Cyclins to start replication. This increases the time expend in G1 and enables the appropriate structuration of the chromatin and of the regulatory network after mitosis and before replication
describe inactive Shh signaling
When hedgehog signaling is not active due to mutation, the hedgehog protein does not bind to the PTCH receptor. So the PTCH inhibits the SMO protein. The SMO protein is degraded in absence of the hedgehog signal. After that the kinases CK1 kinase. PKA and GSK- 3 postulate the Ci protein, and we see phosphorylation of Ci protein, and we have proteolytic cleavage. The SCF complex binds to the Ci protein and mediates the proteolytic cleavage of Ci protein. From this cleavage we get the Ci75 protein, which is the Ci repressor. The CiR gets into the nucleus and targets the DNA, and acts as a transcription repressor for the hedgehog signaling genes
describe the wnt/βcatenin pathway in presence of wnt signal
When there is wnt protein present, it transduces the signal towards the internal components of the pathway, via LRP5/6 and frizzled receptors. At first we have the recruitment of dishevelled (DVL) protein towards the frizzled receptor. Then there is the recruitment of the degradation complex into the plasma membrane where all these degradation complex components get inactivated. The β-catenin in the cytosol remains off from degradation complex and in this way, the β-catenin phosphorylation is blocked. It does not get ubiquitinated and finally the β-catenin is not degraded by proteosome. The unphosphorylated β-catenin accumulates in cytosol and then migrates into the nucleus, where it binds to the LEF/TCF proteins and displaces the GROUCHO complex. Finally, the gene regulatory components are activated and we have expression of WNT genes.
which pathways does the notch delta cross overs with in tumours
Wnt, RAS, NFκB pathways, and promotes the process of carcinogenesis
What is SUFU?
a protein coding gene. it primarily functions as a tumour supressor factor by interacting with and inhibiting glioma associated oncogene homologues
What is a zinc finger?
a small protein structural motif that is characterized by the coordination of one or more zinc ions in order to stabilize the fold which binds to DNA (transcription factor motif)
What is a notochord?
an embryonic midline structure common to all members of the phylum chordata, providing mechanical and signaling cues to the developing embryo
amino acid that stands for X
any amino acid
amino acid that stands for R
arginine
D-type cyclins
associate with cdk's 2, 4, 5,and 6 and promote G0 to G1 transitions and the rate of G1 progression. Cyclin D-cdk4 and cyclin D-cdk6 phosphorylate pRb, which removes the G1 phase block caused by under phosphorylated pRb.
what does the ADAM/TACE do
catalyses the S2 cleavage and generates a substrate for S3 cleavage by the γ-secretase complex
why is the wnt pathway important
cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development.
what does the delta-notch pathway regulate
cell proliferation, cell fate, differentiation and cell death in all metazoans. its been implicated as oncogenic in several cancers including breast cancer and T-cell lymphoblastic leukaemia (T-ALL)
What does phospholipase C do?
cleaves PIP2 into IP3 and DAG
germinalcategories
endoderm (innermost: forms the gut mesoderm (middle): forms the muscles, circulatory system, blood and many different organs ectoderm (outermost): forms the skin and nervous system
Organogenesis
formation of organs. organs start to form from 3 germ layers after gastrulation. - the notochord develops from the mesoderm -the neural tube develops from the ectoderm -the neural tube becomes the brain and spinal cord
how does delta ligand bind to notch receptor
in order for the signaling pathway to become activated the DLL has to bind to the extracellular domain of the notch receptor -DLL becomes activated by a protein within the sending cell: MIB -MIB ubiquinates the DLL for it to become activated and binds to the extracellular domain of the notch receptor
Role of cyclin B1/cdc2 complex
it acts as a maturation/ mitosis- promoting factor in the G2-M phase transition during the cell cycle. Dysregulation of cyclin B1 may be involved in uncontrollable cell growth and malignant transformation
CDK 7
it was discovered as the catalytic subunit of a protein kinase that can activate cdk2. It requires cyclin H as a non-catalytic subunit for activity. The complex of cyclin and cdk is called CAK (cdk-activating kinase) - phosphorylates threonine 161 or corresponding sites in cdk2, cdc2 and cdk4, which is absolutely required for the activity of these kinases.
what is the notch receptor and its ligands?
its ligands are called delta and serrate and they are transmembrane proteins with large extracellular domains that consist primarily of epidermal growth factor (EGF)- like repeats
what do LOF and GOF mutations in β-catenin lead to in inactive wnt pathway
ligand-independent activation
amino acid that stands for K
lysine
in which phase do chromosomes align at the cell equator
metaphase
Cyclin A and B1
mitotic cyclins. A- is synthesised during S phase and degrades during anaphase. During the late stage of S it binds to cdk2 and with cdk1 during G2. Like cyclin E-cdk2 the cyclin A-cdk complex is apparently required for the initiation and progression of DNA replication. Cyclin B1 was the first cyclin identified and is first synthesised during late S with level reaching a maximum during the transition from G2 to M (degraded during anaphase). B1 binds to cdk1 forming a complex that is required to enter mitosis with its degradation required for progression past anaphase. B2 is generally co-expressed with B1. No biochemical or functional differences have been identified between B1 and B2 have been reported for somatic cells, and only minor differences have been described for germ cells.
What is differentiation?
ongoing differentiation in the development of form and structure in the embryo occurs via changes in -cell protein expression -signaling between cells -cell migration -interactions with the extracellular matrix -controlled death (apoptosis)
p16
p16INK4 has also been implicated as a potentially important tumour suppressor gene (MTS1 - homozygous deletion or silencing of promoter region by methylation) as has the related protein p15INK4B (MTS2).
p21WAF1/Cip1
p21WAF1/Cip1 was first identified as a protein co-precipitated with cdk2-cyclin complexes and whose transcription was p53 dependent (in certain instances transcription is p53-independent differentiation specific). It inhibits virtually all cdk's as well as DNA polymerase d.
p27
p27Kip1 was identified as a cdk inhibitor implicated in G1 arrest induced by TGFb and cell-cell contact and has also been shown to be implicated in cell migration (a prerequisite for metastasis) possibly via interaction with the Rho family of proteins. . The p27 molecule differs from p21 in its C terminus; it interacts with similar but not identical cyclin-cdk's and it lacks p53-regulated expression. It potentially inhibits Rb phosphorylation at least by cyclinE-cdk2, Cyclin A-cdk2 and cyclin D1- or D2-cdk4.
amino acid that stands for P
proline
in which phase do duplicated chromosomes attach to the spindle
prometaphase
what does the notch receptor do?
promotes two proteolytic cleavage events in the notch receptor
in which phase do chromosomes condense
prophase
name all mitotic phases
prophase prometaphase metaphase anaphase telophase
which pathways regulate HOX expression
retinol, BMP4, wnt3a
what is hedgehog signaling used for and where did it get its name from
signal transmission from the cell to the nucleus. Sonic Hedgehog (Shh) signalling pathway is one of the major trafficking networks that regulates the key events during developmental processes i.e growth and patterning of multicellular embryos. gene named after the phenotype
the role of Wee1 kinase
the gatekeeper of the G2-M cell cycle checkpoint that allows DNA repair before mitotic entry. Wee1 phosphorylates Cdc2 at Tyr15and inactivates the Cdc2/cyclin B complex, therefore preventing entry into mitosis. hyperphosphorylated Wee1 is isolated from mitotic extracts, and has reduced kinase activity
co-linear expression
the gene order of the HOX cluster in the chromosome with the serial activation of these genes in the oncogenic units along with the anterior-posterior embryonic axis
describe the non-canonical WNT/PCP signaling pathway
the non-canonical WNT/PCP pathway plays a role in the formation of malignancies.
whats cytokinesis
the physical separation into two new daughter cells at the end of mitosis
ES cells in the cell cycle
they are constitutively active, leading to a short, unrestricted G1
describe the wnt/ β-catenin pathway when there is no wnt signal present
this pathway consists of two transmembrane receptors: Frizzled G protein receptor and LRP5/6 receptor (lipoprotein receptor). Both these proteins simultaneously receive extracellular signal in the form of wnt proteins. The β-catenin molecule in the cytosol is the one that transduces the signal and regulates the WNT signal in the pathway. When there is no wnt protein, there is no signal imparted into the cell. The CK1 and GSK3 molecules phosphorylate theβ-catenin protein, which is ubiquitinated and subjected to degradation by proteosomes. To get expression of wnt genes, the β-catenin is needed to displace the Groucho complex. In absence of wnt signal, β-catenin fails to migrate into the nucleus as it got degraded. So the wnt genes cannot be expressed
what does upregulation of ROR/RYK lead to in wnt pathway
uncontrolled activation of WNT signaling
what type of phenotype does Wnt signaling show
wingless phenotype
what does p21 provide
· negative regulator of growth mediates G1 arrest in response to DNA damage blocks re-entry of G2 cells into S-phase G2 block in response to DNA damage ? · counteracts the apoptotic process · differentiation - can be a negative or positive regulator (down regulation occurs in late stages of epithelial, epidermal and osteoblast differentiation) · control of stem cell self-renewal (in keratinocyte and haematopoietic systems)
Mammalian Hox Genes
• 39 Highly conserved Homeobox genes • Organized into 4 different clusters (HoxA, HoxB, HoxC and HoxD) • Each cluster located on a separate chromosome • Up to 13 different paralogs (1-13) per cluster • Encode for transcription factors (Master regulators of development) • Demonstrate spatial expression • 3 genes expressed early in development • 5 genes expressed late in development • Demonstrate co-linear expression • 3 genes expressed anterior • 5 genes expressed posterior
what types of cancer does upregulation of EOE/RYK lead to
• B-cell leukaemia • Chronic lymphocytic leukaemia • Acute lymphoblastic leukaemia • Breast cancer • Gastric cancer • Lung cancer
role of stem cells in CIB
• Chimeric antigen receptor T (CAR-T) cell therapy for cancer patients • Progress hampered by lack of manufacturing process, T cells & TSA. • T cell source used in CAR-T cell therapy is derived predominantly from the patient's own T lymphocytes, which makes this approach impracticable to patients with progressive diseases and T leukemia. • The generation of autologous CAR-T cells is time-consuming due to the lack of readily available T lymphocytes and is not applicable for third-party patients. • Pluripotent stem cells, such as human induced pluripotent stem cells (hiPSCs), can provide an unlimited T cell source for CAR-T cell development with the potential of generating off-the-shelf T cell products. • T-iPSCs (iPSC-derived T cells) are phenotypically defined, expandable, and as functional as physiological T cells. The combination of iPSC and CAR technologies provides an exciting opportunity to oncology and greatly facilitates cell-based therapy for cancer patients. However, T-iPSCs, in combination with CARs, are at the early stage of development and need further preclinical and clinical studies.
Cancer types related to LOF and GOF mutations and inactive WNT signaling
• Colorectal cancer • Breast cancer • Thyroid cancer • Lung cancer • Prostate cancer
Common themes of embryogenesis and cancer
• Embryogenesis requires dramatic changes in cell proliferation, migration and morphogenesis • These features are recapitulated within tumours (EMT) • Elements of key developmental signalling pathways are often mutated or dysregulated in cancer e.g. WNT, NOTCH, HEDGEHOG • Genes that encode transcription factors that are master regulators of development e.g HOX are dysregulated in cancer • Emergin roles for iPSCs in Cancer Immunology and Biotechnology
Development of GVHD in a host using allogeneic T cells.
• Host antigen-presenting cells (APCs), e.g.macrophages or dendritic cells, present alloantigens through MHC class I or class II to donor T cells. • Activated donor T cells recognize host healthy tissues as a foreign antigen and attack and destroy (GVHD). • Can lead to multiple organ failure and life-threatening conditions. • CRISPR/Cas9 genome editing technology used to target HLA and TCR etc. • Donor T cells no longer recognize the host alloantigens as foreign, prevents GVHD development. • As a result, the TCR/HLA knocked-out T cells can act as an off-the-shelf product, viable for different patients.
what types of cancer can LOF mutations lead to in active wnt pathway
• Ovarian cancer • Gastric cancer • Lung cancer • Prostate cancer • Breast cancer
growth factor receptors
•Growth factor receptors can be: -Normal type or mutated (many oncogenic mutations in growth factor receptors) •Growth factors RECEPTOR genes: -Can be mutated so that they can be activated in a ligand-independent manor à causes inappropriate activation of downstream proteins (called signal transduction molecules), also increased expression via amplification (HER2). Example: c-KIT is a growth factor receptor
growth factors act as
•Hormones -act at a distance •Paracrine factors -act locally •Juxtacrine factors -act through cell-cell contact •Autocrine factors -act on the same cell •Intracrine factors -act intracellularly
kinase regulation
•Most kinases are associated with phosphatases (enzymes that regulate dephosphorylation) •Transmembrane receptor kinases have flanking amino acids to recruit second messengers •The 'signal particle' is also dependent upon cell type •This process is highly regulable by adaptor proteins which act as scaffolds to signalling networks (discussed later).
signaling transfer through phosphorylation
•Phosphorylation -Transfer of high energy phosphate group from ATP or GTP to a protein is catalysed by kinases -Phosphate is added to tyrosine, serine or threonine -Performed by specific kinases -Alters the conformation in important regions altering the proteins function -Acts as a molecular switch (activating/inactivating)
